Progesterone phosphate analogs and uses related thereto

ABSTRACT

This disclosure relates to progesterone phophate derivatives and uses related thereto. In certain embodiments, the disclosure relates to compounds disclosed herein and uses for managing inflammation such as those resulting from traumatic brain injury or stroke.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/728,459 filed Oct. 9, 2017, which is a continuation of U.S.application Ser. No. 14/911,807 filed Feb. 12, 2016, now issued as U.S.Pat. No. 9,802,978 on Oct. 31, 2017, which is the National Stage ofInternational Application Number PCT/US2014/050565 filed Aug. 11, 2014,which claims priority to U.S. Provisional Application No. 61/864,681filed Aug. 12, 2013. The entirety of each of these applications ishereby incorporated by reference for all purposes.

FIELD

This disclosure relates to progesterone phosphate derivatives and usesrelated thereto. In certain embodiments, the disclosure relates tocompounds disclosed herein and uses for managing inflammation such asthose resulting from traumatic brain injury or stroke.

BACKGROUND

Brain injuries, including traumatic brain injury (TBI) and stroke,affect well over 2 million Americans each year and are a significanthealth concern worldwide. Traumatic brain injuries result from a blow orjolt to the head or a penetrating head injury that disrupts the functionof the brain, with severity ranging from “mild,” i.e., a brief change inmental status or consciousness to “severe,” i.e., an extended period ofunconsciousness or amnesia after the injury. In contrast, strokes are aresult of diseases that affect the blood vessels that supply blood tothe brain. A stroke occurs when a blood vessel that brings oxygen andnutrients to the brain either bursts (hemorrhagic stroke) or is cloggedby a blood clot or some other mass (ischemic stroke). The majority ofstrokes are ischemic, however hemorrhagic strokes typically result inmore severe injuries.

Despite several decades of effort, scientists have not yet found apharmacological agent that consistently improves outcomes after strokeor TBI (see Sauerland, S. et al., Lancet 2004, 364, 1291-1292; BrainTrauma Foundation, American Association of Neurological Surgeons, JointSection on Neurotrauma and Critical Care. Guidelines for the managementof severe head injury. J. Neurotrauma 1996, 13, 641-734).

After TBI or stroke, inflammation is a principle cause of secondarydamage and long-term damage. Following insults to the central nervoussystem, a cascade of physiological events leads to neuronal lossincluding, for example, an inflammatory immune response andexcitotoxicity resulting from disrupting the glutamate, acetylcholine,cholinergic, GABAA, and NMDA receptor systems. In these cases, a complexcascade of events leads to the delivery of blood-borne leucocytes tosites of injury to kill potential pathogens and promote tissue repair.However, the powerful inflammatory response has the capacity to causedamage to normal tissue, and dysregulation of the innate, or acquiredimmune response is involved in different pathologies.

In addition to TBI and stroke, inflammation is being recognized as a keycomponent of a variety of nervous system disorders. It has long beenknown that certain diseases such as multiple sclerosis result frominflammation in the central nervous system, but it is only in recentyears that it has been suggested that inflammation may significantlycontribute to neurodegenerative disoders such as HIV-related dementia,Alzheimer's and prion diseases. It is now known that the residentmacrophages of the central nervous system (CNS), the microglia, whenactivated may secrete molecules that cause neuronal dysfunction, ordegeneration.

There is growing experimental evidence that progesterone, itsmetabolites and other gonadal steroids such as estrogen and possiblytestosterone, are effective neuroprotective agents. Pre-clinical andclinical research demonstrates that the hormone progesterone is a potentneurosteroid that, acutely administered, can dramatically reducecerebral edema, inflammation, tissue necrosis, and programmed cell death(see Djebaili, M. et al, J. Neurotrauma 2005, 22, 106-118; Pettus, E. H.et al, Brain Res. 2005, 1049, 112-119; Grossman, K. J. et al, Brain Res,2004, 1008, 29-39; He, J. et al, Exp. Neurol 2004, 189, 404-412; He, J.et al, Restor. Neurol Neurosci. 2004, 22, 19-31; Djebaili, M. et al, J.Neuroscience 2004, 123, 349-359; Hoffman, S. W. et al, Academy ofEmergency Medicine, 2001, 8, 496-497; and Wright, D. W. et al, J.Neurotrauma. 2001, 18, 901-909).

In vivo data has demonstrated progesterone's neuroprotective effects ininjured nervous systems. For example, following a contusion injury,progesterone reduces the severity of post injury cerebral edema. Theattenuation of edema by progesterone is accompanied by the sparing ofneurons from secondary neuronal death and improvements in cognitiveoutcome (Roof et al. (1994) Experimental Neurology 129:64-69).Furthermore, following ischemic injury in rats, progesterone has beenshown to reduce cell damage and neurological deficit (Jiang et al.(1996) Brain Research 735:101-107). A Phase II, single-center,controlled trial involving 100 moderate to severe TBI patients showedthat 3 days of intravenous progesterone treatment reduced mortality byover 60% and significantly improved functional outcomes at 30 dayspost-injury (see Wright, D. A. et al., Ann. Emerg. Med. 2007, 49, 391).

PCT Publication WO 2002/30409 to Emory University provides methods forconferring a neuroprotective effect on a population of cells in asubject following a traumatic injury to the central nervous system byadministration of a progestin or progestin metabolite following atraumatic brain injury.

PCT Publication WO 2006/102644 also to Emory University provides methodsfor the treatment or the prevention of neuronal damage in the CNS bytapered administration of a progestin or progestin metabolite followinga traumatic or ischemic injury to the CNS to avoid withdrawal.

PCT Publication No. WO 2006/102596 to Emory University provides certainmethods of treating a subject with a traumatic central nervous systeminjury, more particularly, a traumatic brain injury that include atherapy comprising a constant or a two-level dosing regime ofprogesterone.

PCT Publication No. WO 2009/108804 to Emory University provides certainmethods of treating a subject with a traumatic central nervous systeminjury. It also discloses certain progesterone analogs.

Studies have indicated that progesterone may be useful in treating orpreventing neurodegeneration following stroke (see Stein, D. (2005) TheCase for Progesterone US Ann. N. Y. Acad. ScL. 1052:152-169; Murphy, etal. (2002) Progesterone Administration During Reperfusion, But NotPreischemia Alone, Reduces Injury in Ovariectomized Rats. J. Cereb.Blood Flow & Metab. 22:1181-1188; Murphy, et al. (2000) ProgesteroneExacerbates Striatal Stroke Injury in Progesterone-Deficient FemaleAnimals. Stroke 31: 1173).

U.S. Pat. No. 6,245,757, now expired, to Research CorporationTechnologies, Inc. provides a method for the treatment of ischemicdamage, such as damage due to stroke or myocardial infarction comprisingadministering to a mammal afflicted with stroke an effective amount of aneuroprotective steroid in a suitable vehicle.

In addition to being a gonadal steroid, progesterone also belongs to afamily of autocrine/paracrine hormones called neurosteroids.Neurosteroids are steroids that accumulate in the brain independently ofendocrine sources and which can be synthesized from sterol precursors innervous cells. These neurosteroids can potentiate GABA transmission,modulate the effects of glutamate, enhance the production of myelin, andprevent release of free radicals from activated microglia.

Various metabolites of progesterone have also been thought to haveneuroprotective properties. For instance, the progesterone metabolitesallopregnanolone or epipregnanolone are positive modulators of the GABAreceptor, increasing the effects of GABA in a manner that is independentof the benzodiazepines (Baulieu, E. E. (1992) Adv. Biochem.Psychopharmacol. 47:1-16; Robel et al. (1995) Crit. Rev. Neurobiol.9:383-94; Lambert et al. (1995) Trends Pharmacol. ScL 16:295-303;Baulieu, E. E. (1997) Recent Prog. Horm. Res. 52:1-32; Reddy et al.(1996) Psychopharmacology 128:280-92). In addition, these neurosteroidsact as antagonists at the sigma receptor, which can activate the NMDAchannel complex (Maurice et al. (1998) Neuroscience 83:413-28; Mauriceet al. (1996) J. Neurosci. Res. A(3:1M-A7>; Reddy et al. (1998)Neuroreport 9:3069-73). These neurosteroids have also been shown toreduce the stimulation of cholinergic neurons and the subsequent releaseof acetylcholine by excitability. Numerous studies have shown that thecholinergic neurons of the basal forebrain are sensitive to injury andthat excessive release of acetylcholine can be more excitotoxic thanglutamate (Lyeth et al. (1992) J. Neurotrauma 9(2):S463-74; Hayes et al.(1992) J. Neurotrauma 9(1):S173-87).

As discussed above, following a traumatic injury to the central nervoussystem, a cascade of physiological events leads to neuronal loss. Inaddition, the injury is frequently followed by brain and/or spinal cordedema that enhances the cascade of injury and leads to further secondarycell death and increased patient mortality. Methods are needed for thein vivo treatment of traumatic CNS injuries that are successful atproviding subsequent trophic support to remaining central nervous systemtissue, and thus enhancing functional repair and recovery, under thecomplex physiological cascade of events which follow the initial insult.

TBI produces a complex succession of molecular events in addition to theimmediate loss of nervous tissue caused by concussions, contusions andballistic injuries. The “brain injury cascade” initiates rapidly afterthe initial trauma and unfolds over days, weeks and even months.Therefore, an important tenet of brain injury treatment is that thesooner one can treat/prevent edema, inflammation and neuronal loss, thebetter the functional outcome will be. Current clinical protocols forthe use of progesterone occur once patients are transported to ahospital setting, thus losing valuable time before the treatment can beadministered. As a natural product, progesterone is insoluble inaqueous-based formulations, and is typically delivered in a freshlyprepared lipid formulation, a fairly complicated and time-consumingpreparation. Furthermore, the plasma half-life of progesterone islimited, so treatment typically institutes a continuous i.v. drip, ormultiple injections with an oil-based formulation delaying release tothe systemic circulation. Thus there is a need for an improved treatmentfor TBI that can be administered easily and rapidly.

US Patent Application Publication number, US20130210785 reportsprogesterone analogues.

References cited herein are not an admission of prior art.

SUMMARY

This disclosure relates to progesterone phosphate derivatives and usesrelated thereto. In certain embodiments, the disclosure relates tocompounds disclosed herein and uses for managing inflammation such asthose resulting from traumatic brain injury or stroke. In certainembodiments, the disclosure relates to compounds of Formula I

or esters, prodrugs, or salts thereof wherein

X is O, N—OR¹⁰, or N—OCR¹R²OPZ(OR³)₂;

Y is O, N—OR¹⁰, or N—OCR¹R²OPZ(OR³)₂; provided at least one X or Y isN—OCR¹R²OPO(OR³)₂;

Z is ═O or ═S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

each R³ is independently and individually phosphate ion, hydrogen,—CH₂O(C═O)alkyl, or a group selected from alkyl, alkanoyl, and formylfurther substituted with one or more, the same or different, alkyl,amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl,wherein R³ is optionally substituted with one or more, the same ordifferent, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R⁴ is optionally substituted with one ormore, the same or different, R⁵;

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

R¹⁰ is hydrogen or a group selected from alkyl and formyl furthersubstituted with one or more, the same or different, alkyl, amino,hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, whereinR¹⁰ is optionally substituted with one or more, the same or different,R²⁰;

R²⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one ormore, the same or different, R³⁰;

R³⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R³⁰ is optionally substituted with one ormore, the same or different, R⁴⁰; and

R⁴⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-di ethylsulfamoyl, N-methyl-N-ethylsulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to pharmaceuticalcompositions comprising a compound disclosed herein and apharmaceutically acceptable excipient. The pharmaceutical compositionmay optionally further comprise a second active therapeutic agent.

In certain embodiments, the disclosure relates to methods of treating orpreventing inflammation comprising administering an effective amount ofa compound or a pharmaceutical composition comprising a compounddisclosed herein to a subject in need thereof. In certain embodiments,the pharmaceutical composition is administered to a subject thatincurred trauma to the head or other organ or tissue. In certainembodiments, the pharmaceutical composition is administered after amedical procedure. In certain embodiments, the pharmaceuticalcomposition is administered in combination with a secondanti-inflammatory agent.

In certain embodiments, the disclosure relates to methods of treatingstroke or traumatic brain injury comprising administering an effectiveamount of a compound or a pharmaceutical composition comprising acompound disclosed herein to a subject in need thereof.

In other embodiments, the disclosure relates to methods of treating orpreventing neurodegeneration resulting from ischemic CNS injuries, inparticular from ischemic stroke comprising administering a compounddisclosed herein to a patient in need thereof.

In yet other embodiments, the disclosure relates to methods of treatingor preventing neurodegeneration resulting from hemorrhagic CNS injuries,in particular from hemorrhagic stroke comprising administering acompound disclosed herein to a patient in need thereof. The methods canalleviate the initial damage to the CNS. Therefore, in some embodiments,the compounds are administered to a patient at risk of a CNS injury, inparticular to a patient at risk of a stroke. The compounds are alsoeffective at reducing or preventing secondary injuries. Therefore, inother embodiments, the compounds are administered to a patient who hassuffered a CNS injury within a window of opportunity after the initialinsult. The initial insult can be either a TBI or a stroke, whether thatbe an ischemic or hemorrhagic stroke.

In certain embodiments, the disclosure relates to methods of treating orpreventing a neurodegenerative disease or condition comprisingadministering an effective amount of a pharmaceutical composition to asubject in need thereof, e.g., at risk of, exhibiting symptoms of, ordiagnosed with the disease or condition. Contemplated neurodegenerativediseases or conditions include, but are not limited to, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, multiple sclerosis,amyotrophic lateral sclerosis, dementia, extrapyramidal and movementdisorders, motor neurone disease, systemic atrophies primarily affectingthe central nervous system, Tay-Sachs disease, ataxia telangiectasia,Batten disease, corticobasal degeneration, Creutzfeldt-Jakob disease,fatal familial insomnia, infantile Refsum disease, lyme disease,Machado-Joseph disease, multiple system atrophy, neuroacanthocytosis,Niemann-Pick disease, refsum disease, Sandhoff disease, Shy-Dragersyndrome, spinocerebellar ataxia, tabes dorsalis, toxic encephalopathy,and Wobbly hedgehog syndrome.

Pharmaceutical compositions, including in combination with additionalneuroprotective agents, are also provided.

In certain embodiments, the disclosure relates to the production of amedicament for uses disclosed herein.

In certain embodiments, the disclosure relates to methods of makingcompounds disclosed herein comprising mixing starting materialsdisclosed herein to form compounds disclosed herein.

In certain embodiment, the disclosure relates to compounds disclosedherein and derivatives such as the compounds substituted with one ormore substituents and salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates certain embodiments of the disclosure. R²=H, methyl,ethyl; R³=H, methyl, ethyl; or R² and R³ together=methylene groupsbonded to one another forming a cyclopropyl ring: —H₂C—CH₂—; X=H, Li⁺,Na⁺, K⁺, trialkylammonium or other pharmaceutically acceptable cationswith +1 charge; Y=H, Li⁺, Na⁺, K⁺, trialkylammonium or otherpharmaceutically acceptable cations with +1 charge; or X and Ytogether=Ca²⁺, Mg²⁺, or other pharmaceutically acceptable cations with+2 charge.

FIG. 2 illustrated certain embodiments of the disclosure.

FIG. 3 illustrates the preparation of certain embodiments of thedisclosure.

FIG. 4 illustrates the preparation of certain embodiments of thedisclosure.

FIG. 5 shows data of IV, IM, and PO dosing of EPRX01723 in rat plasma.The pharmacokinetics of EPRX-1723 (POM derivative of C-20 oxime) wasdetermined after IM dosing at 3 different levels and showed exposure ofthe relative C-20 oxime parent (EPRX-036) indicating that thesolubilizing prodrug is efficiently cleaved in vivo to give the activeparent oxime. Diamond represents PO (30 mg/kg), orange box represents IM(3 mg/kg), green triangle represents IM (10 mg/kg), yellow boxrepresents IM (30 mg/kg), brown box represents IV (2 mg/kg), red circlerepresents IM (0 mg/kg).

DETAILED DESCRIPTION

Before the present disclosure is described in greater detail, it is tobe understood that this disclosure is not limited to particularembodiments described, and as such may, of course, vary. It is also tobe understood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present disclosure will be limited onlyby the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure, the preferredmethods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present disclosure is not entitled to antedate suchpublication by virtue of prior disclosure. Further, the dates ofpublication provided could be different from the actual publicationdates that may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure. Any recited method can be carried out in the order of eventsrecited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwiseindicated, techniques of medicine, organic chemistry, biochemistry,molecular biology, pharmacology, and the like, which are within theskill of the art. Such techniques are explained fully in the literature.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. In this specification andin the claims that follow, reference will be made to a number of termsthat shall be defined to have the following meanings unless a contraryintention is apparent.

Prior to describing the various embodiments, the following definitionsare provided and should be used unless otherwise indicated. As usedherein, the terms “prevent” and “preventing” include the prevention ofthe recurrence, spread or onset. It is not intended that the presentdisclosure be limited to complete prevention. In some embodiments, theonset is delayed, or the severity of the disease is reduced.

As used herein, the terms “treat” and “treating” are not limited to thecase where the subject (e.g., patient) is cured and the disease iseradicated. Rather, embodiments, of the present disclosure alsocontemplate treatment that merely reduces symptoms, and/or delaysdisease progression.

As used herein, the term “combination with” when used to describeadministration with an additional treatment means that the agent may beadministered prior to, together with, or after the additional treatment,or a combination thereof.

As used herein, “alkyl” means a noncyclic straight chain or branched,unsaturated or saturated hydrocarbon such as those containing from 1 to10 carbon atoms, while the term “lower alkyl” or “C₁₋₄alkyl” has thesame meaning as alkyl but contains from 1 to 4 carbon atoms. The term“higher alkyl” has the same meaning as alkyl but contains from 7 to 20carbon atoms. Representative saturated straight chain alkyls includemethyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl,n-nonyl, and the like; while saturated branched alkyls includeisopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.Unsaturated alkyls contain at least one double or triple bond betweenadjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”,respectively). Representative straight chain and branched alkenylsinclude ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,2,3-dimethyl-2-butenyl, and the like; while representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

Non-aromatic mono or polycyclic alkyls are referred to herein as“carbocycles” or “carbocyclyl” groups. Representative saturatedcarbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and the like; while unsaturated carbocycles include cyclopentenyl andcyclohexenyl, and the like.

“Heterocarbocycles” or heterocarbocyclyl” groups are carbocycles whichcontain from 1 to 4 heteroatoms independently selected from nitrogen,oxygen and sulfur which may be saturated or unsaturated (but notaromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfurheteroatoms may be optionally oxidized, and the nitrogen heteroatom maybe optionally quaternized. Heterocarbocycles include morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“Aryl” means an aromatic carbocyclic monocyclic or polycyclic ring suchas phenyl or naphthyl. Polycyclic ring systems may, but are not requiredto, contain one or more non-aromatic rings, as long as one of the ringsis aromatic.

As used herein, “heteroaryl” refers an aromatic heterocarbocycle having1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, andcontaining at least 1 carbon atom, including both mono- and polycyclicring systems. Polycyclic ring systems may, but are not required to,contain one or more non-aromatic rings, as long as one of the rings isaromatic. Representative heteroaryls are furyl, benzofuranyl,thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl,pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl,pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that theuse of the term “heteroaryl” includes N-alkylated derivatives such as a1-methylimidazol-5-yl substituent.

As used herein, “heterocycle” or “heterocyclyl” refers to mono- andpolycyclic ring systems having 1 to 4 heteroatoms selected fromnitrogen, oxygen and sulfur, and containing at least 1 carbon atom. Themono- and polycyclic ring systems may be aromatic, non-aromatic ormixtures of aromatic and non-aromatic rings. Heterocycle includesheterocarbocycles, heteroaryls, and the like.

“Alkylthio” refers to an alkyl group as defined above attached through asulfur bridge. An example of an alkylthio is methylthio, (i.e., —S—CH₃).

“Alkoxy” refers to an alkyl group as defined above attached through anoxygen bridge. Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy,n-propoxy, propoxy, n-butoxy, s-butoxy, t-butoxy.

“Alkylamino” refers an alkyl group as defined above attached through anamino bridge. An example of an alkylamino is methylamino, (i.e.,—NH—CH₃).

“Alkanoyl” refers to an alkyl as defined above attached through acarbonyl bride (i.e., —(C═O)alkyl).

“Alkylsulfonyl” refers to an alkyl as defined above attached through asulfonyl bridge (i.e., —S(═O)₂alkyl) such as mesyl and the like, and“Arylsulfonyl” refers to an aryl attached through a sulfonyl bridge(i.e., —S(═O)₂aryl).

“Alkylsulfinyl” refers to an alkyl as defined above attached through asulfinyl bridge (i.e. —S(═O)alkyl).

The term “substituted” refers to a molecule wherein at least onehydrogen atom is replaced with a substituent. When substituted, one ormore of the groups are “substituents.” The molecule may be multiplysubstituted. In the case of an oxo substituent (“═O”), two hydrogenatoms are replaced. Example substituents within this context may includehalogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl,carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, —NR_(a)R_(b), —NR_(a)C(═O)R_(b),—NR_(a)C(═O)NR_(a)NR_(b), —NR_(a)C(═O)OR_(b)— NR_(a)SO₂R_(b),—C(═O)R_(a), —C(═O)OR_(a), —C(═O)NR_(a)R_(b), —OC(═O)NR_(a)R_(b),—OR_(a), —SR_(a), —SOR_(a), —S(═O)₂R_(a), —OS(═O)₂R_(a) and—S(═O)₂OR_(a). R_(a) and R_(b) in this context may be the same ordifferent and independently hydrogen, halogen hydroxyl, alkyl, alkoxy,alkyl, amino, alkylamino, dialkyl amino, carbocyclyl, carbocycloalkyl,heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl.

The term “optionally substituted,” as used herein, means thatsubstitution is optional and therefore it is possible for the designatedatom to be unsubstituted.

As used herein, “salts” refer to derivatives of the disclosed compoundswhere the parent compound is modified making acid or base salts thereof.Examples of salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines, alkylamines, ordialkylamines; alkali or organic salts of acidic residues such ascarboxylic acids and phosphates; and the like. In preferred embodimentthe salts are conventional nontoxic pharmaceutically acceptable saltsincluding the quaternary ammonium salts of the parent compound formed,and non-toxic inorganic or organic acids. Preferred salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like. In certainembodiments, the compounds herein are phosphate salts with a positiveone or two metal cation such as sodium, lithium, potassium, quaternaryammonium, calcium, magnesium, or combinations thereof.

“Subject” refers any animal, preferably a human patient, livestock,rodent, primate, monkey, or domestic pet.

The term “prodrug” refers to an agent that is converted into abiologically active form in vivo. Prodrugs are often useful because, insome situations, they may be easier to administer than the parentcompound. They may, for instance, be bioavailable by oral administrationwhereas the parent compound is not. The prodrug may also have improvedsolubility in pharmaceutical compositions over the parent drug. Aprodrug may be converted into the parent drug by various mechanisms,including enzymatic processes and metabolic hydrolysis.

As used herein, the term “derivative” refers to a structurally similarcompound that retains sufficient functional attributes of the identifiedanalogue. The derivative may be structurally similar because it islacking one or more atoms, substituted, a salt, in differenthydration/oxidation states, or because one or more atoms within themolecule are switched, such as, but not limited to, replacing an oxygenatom with a sulfur or nitrogen atom or replacing an amino group with ahydroxyl group or vice versa. The derivative may be a prodrug.Derivatives may be prepare by any variety of synthetic methods orappropriate adaptations presented in synthetic or organic chemistry textbooks, such as those provide in March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) MichaelB. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F.Tietze hereby incorporated by reference.

PROG, Progesterone; TBI, traumatic brain injury; EDCI,N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; DMAP,4-dimethylaminopyridine.

Compounds

In certain embodiments, the disclosure relates to compounds of Formula I

or esters, prodrugs, or salts thereof wherein

X is O, N—OR¹⁰, or N—OCR¹R²OPZ(OR³)₂;

Y is O, N—OR¹⁰, or N—OCR¹R²OPZ(OR³)₂; provided at least one X or Y isN—OCR¹R²OPO(OR³)₂;

Z is ═O or ═S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

each R³ is independently and individually individually phosphate ion,hydrogen, —CH₂O(C═O)alkyl, or a group selected from alkyl, alkanoyl, andformyl further substituted with one or more, the same or different,alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, orheterocyclyl, wherein R³ is optionally substituted with one or more, thesame or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R⁴ is optionally substituted with one ormore, the same or different, R⁵;

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl —N-ethyl amino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

R¹⁰ is hydrogen or a group selected from alkyl and formyl furthersubstituted with one or more, the same or different, alkyl, amino,hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, whereinR¹⁰ is optionally substituted with one or more, the same or different,R²⁰;

R²⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one ormore, the same or different, R³⁰;

R³⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R³⁰ is optionally substituted with one ormore, the same or different, R⁴⁰; and

R⁴⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl —N-ethyl amino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, X is N—OCR¹R²OPZ(OR³)₂ and Y is O or N—OR^(m).

In certain embodiments, Y is N—OCR¹R²OPZ(OR³)₂ and X is O or N—OR^(m).

In certain embodiments, R¹ and R² are hydrogen or alkyl.

In certain embodiments, R¹ and R² form a cyclopropyl ring.

In certain embodiments, R³ is phosphate ion, hydrogen, alkanoyl, oralkyl, wherein R³ is optionally substituted with one or more, the sameor different, R⁴;

In certain embodiments, the compounds are phosphate salts with apositive one or two metal cation such as sodium, lithium, potassium,quaternary ammonium, calcium, magnesium, or combinations thereof.

In certain embodiments, the disclosure relates to compounds of formula Ihaving formula IA

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl —N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to compounds of FormulaD3

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl —N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

R¹⁰ is hydrogen or a group selected from alkyl and formyl substitutedwith one or more, the same or different, alkyl, amino, hydroxyl, thiol,halogen, aryl, carbocyclyl, or heterocyclyl, wherein R¹⁰ is optionallysubstituted with one or more, the same or different, R²⁰;

R²⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R²⁰ is optionallysubstituted with one or more, the same or different, R³⁰;

R³⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R³⁰ is optionallysubstituted with one or more, the same or different, R⁴⁰; and

R⁴⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl —N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-di methylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula IC

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

R²⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one ormore, the same or different, R³⁰;

R³⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R³⁰ is optionallysubstituted with one or more, the same or different, R⁴; and

R⁴⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dim ethylamino, diethylamino, N-methyl —N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to compounds of formulaIC, wherein R²⁰ is heterocyclyl or alkyl substituted with a groupselected from amino and heterocyclyl, wherein R²⁰ is optionallysubstituted with one or more, the same or different, R³⁰.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula ID

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R¹ is optionally substitutedwith one or more, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R² is optionally substitutedwith one or more, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl —N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

n is 1, 2, 3, or 4;

R⁵⁰ and R⁶⁰ and the attached nitrogen form a 5 or 6 memberedheterocyclyl optionally substituted with one or more, the same ordifferent, R⁷⁰; or

R⁵⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R⁵ is optionally substituted with one ormore, the same or different, R⁷⁰;

R⁶⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R⁶⁰ is optionally substituted with one ormore, the same or different, R⁷⁰;

R⁷⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁷⁰ is optionallysubstituted with one or more, the same or different, R⁸⁰; and

R⁸⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dim ethylamino, diethylamino, N-methyl —N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula IE

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R¹ is optionally substitutedwith one or more, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R² is optionally substitutedwith one or more, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl —N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

m is 1, 2, 3, or 4;

R⁹ and R¹⁰ and the attached nitrogen form a 5 or 6 membered heterocyclyloptionally substituted with one or more, the same or different, R¹¹; or

R⁹ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R⁹ is optionally substituted with one ormore, the same or different, R¹¹;

R¹⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R¹⁰ is optionally substituted with one ormore, the same or different, R¹¹;

R¹¹ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹¹ is optionally substituted with one ormore, the same or different, R¹²; and

R¹² is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethylamino, dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, m is 0 or 1.

In certain embodiments, m is 2 or 3.

In certain embodiments, R⁹ and R¹⁰ is morpholinyl, pyrrolidinyl,piperidinyl, or piperazinyl ring optionally substituted with one ormore, the same or different, R¹¹.

In certain embodiments, R⁹ and R¹⁰ is morpholinyl, pyrrolidinyl,piperidinyl, or piperazinyl ring further substituted with one or more,the same or different, R¹¹.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula IF

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

R¹³ and R¹⁴ are the same or different alkyl optionally substituted withone or more, the same or different, R¹⁵; or

R¹³ and R¹⁴ and the attached carbon form a 5 or 6 membered aryl orheterocyclyl optionally substituted with one or more, the same ordifferent, R¹⁵;

R¹⁵ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹⁵ is optionally substituted with one ormore, the same or different, R¹⁶; and

R¹⁶ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dim ethylamino, diethylamino, N-methyl —N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, R¹³ and R¹⁴ is morpholinyl, piperidinyl, orpiperazinyl ring optionally substituted with one or more, the same ordifferent, R¹⁵.

In certain embodiments, R¹³ and R¹⁴ is morpholinyl, pyrrolidinyl,piperidinyl, or piperazinyl ring further substituted with one or more,the same or different, R¹⁵.

In certain embodiments, R¹³ and R¹⁴ is an aromatic heterocyclyl such aspyridinyl

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula IG

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the oxime composition is in greater than 60, 70,80, 90, or 95% of the E or Z configuration. Certain embodiments areexemplified below.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula IH

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R⁴ is optionally substituted with one ormore, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

R¹⁰ is hydrogen or a group selected from alkyl and formyl substitutedwith one or more, the same or different, alkyl, amino, hydroxyl, thiol,halogen, aryl, carbocyclyl, or heterocyclyl, wherein R¹⁰ is optionallysubstituted with one or more, the same or different, R²⁰;

R²⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one ormore, the same or different, R³⁰;

R³⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R³⁰ is optionally substituted with one ormore, the same or different, R⁴⁰; and

R⁴⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl —N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-di methylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula II

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl —N-ethylamino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

R²⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one ormore, the same or different, R³⁰;

R³⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R³⁰ is optionallysubstituted with one or more, the same or different, R⁴⁰; and

R⁴⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl —N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to compounds of formulaII, wherein R²⁰ is heterocyclyl or alkyl substituted with a groupselected from amino and heterocyclyl, wherein R²⁰ is optionallysubstituted with one or more, the same or different, R³⁰.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula IJ

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl —N-ethyl amino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

n is 1, 2, 3, or 4;

R⁵⁰ and R⁶⁰ and the attached nitrogen form a 5 or 6 memberedheterocyclyl optionally substituted with one or more, the same ordifferent, R⁷⁰; or

R⁵⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R⁵⁰ is optionally substituted with one ormore, the same or different, R⁷⁰;

R⁶⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R⁶⁰ is optionally substituted with one ormore, the same or different, R⁷⁰;

R⁷⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁷⁰ is optionallysubstituted with one or more, the same or different, R⁸⁰; and

R⁸⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl —N-ethyl amino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, n is 1.

In certain embodiments, n is 2 or 3.

In certain embodiments, R⁵⁰ and R⁶⁰ is morpholinyl, pyrrolidinyl,piperidinyl, or piperazinyl ring optionally substituted with one ormore, the same or different, R⁷⁰.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula IK

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R⁴ is optionally substituted with one ormore, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

m is 1, 2, 3, or 4;

R⁹ and R¹⁰ and the attached nitrogen form a 5 or 6 membered heterocyclyloptionally substituted with one or more, the same or different, R^(H);or

R⁹ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R⁹ is optionally substituted with one ormore, the same or different, R^(H);

R¹⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R¹⁰ is optionally substituted with one ormore, the same or different, R^(H);

R¹¹ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹¹ is optionally substituted with one ormore, the same or different, R¹²; and

R¹² is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethylamino, dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, m is 0 or 1.

In certain embodiments, m is 2 or 3.

In certain embodiments, R⁹ and R¹⁰ is morpholinyl, pyrrolidinyl,piperidinyl, or piperazinyl ring optionally substituted with one ormore, the same or different, R¹¹.

In certain embodiments, R⁹ and R¹⁰ is morpholinyl, pyrrolidinyl,piperidinyl, or piperazinyl ring further substituted with one or more,the same or different, R¹¹.

In certain embodiments, the disclosure relates to compounds of formula Ihaving Formula IL

or esters, prodrugs, or salts thereof wherein

Z is ═O or =S;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R² is optionally substitutedwith one or more, the same or different, R⁴; or

R¹ and R² form a carbocyclic ring;

R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴;

R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selectedfrom alkyl, alkanoyl, and formyl further substituted with one or more,the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R^(3′) is optionally substitutedwith one or more, the same or different, R⁴;

R⁴ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionally substitutedwith one or more, the same or different, R⁵; and

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethyl amino,dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl;

R¹³ and R¹⁴ are the same or different alkyl optionally substituted withone or more, the same or different, R¹⁵; or

R¹³ and R¹⁴ and the attached carbon form a 5 or 6 membered aryl orheterocyclyl optionally substituted with one or more, the same ordifferent, R¹⁵;

R¹⁵ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R¹⁵ is optionallysubstituted with one or more, the same or different, R¹⁶; and

R¹⁶ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methyl amino, ethylamino, dim ethyl amino, di ethyl amino, N-methyl-N-ethyl amino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl.

Methods of Use Treatment of CNS Damage

In certain embodiments, the disclosure relates to methods andcompositions for the treatment or prevention of neurodegenerationfollowing an injury to the central nervous system or due to certainneurodegenerative disorders comprising administering an effective amountof a compound described herein, or a pharmaceutically acceptable salt,ester or prodrug thereof to a subject in need thereof. Multiplephysiological events lead to neurodegeneration. These events include,for example, increase in the immune and inflammatory response,demyelinization, and lipid peroxidation. In certain embodiments, thedisclosure relates to compositions and methods for reducing oreliminating neuronal cell death, edema, ischemia, and enhancing tissueviability following injury to the central nervous system or certaindisorders. The analogues, salts, esters or prodrugs of the, compound,steroid, or secosteroid analogs may be optionally administered with apharmaceutically acceptable carrier or diluent.

As used herein, “neuroprotection” is the prevention, arrest or reverseprogression of neurodegeneration following a central nervous systeminjury. The neuroprotective effect includes both improved morphological(i.e., enhanced tissue viability) and/or behavioral recovery. CNSinjuries that are encompassed within the scope of treatment include bothtraumatic injuries, in particular TBI, and physiological insults such asan ischemic or hemorrhagic stroke. In both instances, a progressive lossof neurons after the initial insult occurs and can be alleviated.

In certain embodiments, the disclosure relates to methods of preventingor reducing inflammatory reactions in a patient by administering acompound disclosed herein to a subject in need thereof. In certainembodiments, methods of neuroprotection are provided comprisingadministering a compound disclosed herein, its physiologicallyacceptable salt or prodrug, optionally in a pharmaceutically acceptablecarrier, to a patient at risk of suffering from a stroke. In otherembodiments, methods of treating or preventing neuronal damage areprovided comprising administering a compound disclosed herein or itsphysiologically acceptable salt or prodrug, optionally in apharmaceutically acceptable carrier, to a patient who has suffered froman ischemic stroke. The method can reduce or prevent neurodegenerationsuch as that caused by excitotoxic or inflammatory reactions, or canenhance neuronal proliferation, growth or differentiation in the periodafter the injury. In yet further embodiments, methods of treating orpreventing cognitive or behavioral deficits after a stroke is providedcomprising administering a compound disclosed herein or itsphysiologically acceptable salt or prodrug, optionally in apharmaceutically acceptable carrier, to a human subject who has suffereda stroke. In certain embodiments, the stroke is an ischemic stroke, butit can alternatively be a hemorrhagic stroke.

In other embodiments, the present disclosure relates to methods toachieve a neuroprotective effect following a traumatic CNS injury in amammal, in particular in a human, comprising administering atherapeutically effective amount of a compound disclosed herein. Atraumatic injury to the CNS is characterized by a physical impact to thecentral nervous system. The physical forces resulting in a traumaticbrain injury cause their effects by inducing three types of injury:skull fracture, parenchymal injury, and vascular injury. A blow to thesurface of the brain typically leads to rapid tissue displacement,disruption of vascular channels, and subsequent hemorrhage, tissueinjury and edema. Morphological evidence of injury in the neuronal cellbody includes pyknosis of nucleus, eosinophilia of the cytoplasm, anddisintegration of the cell. Furthermore, axonal swelling can develop inthe vicinity of damage neurons and also at great distances away from thesite of impact.

In certain embodiments, the compound is administered within twelve hoursafter onset of a stroke. In certain embodiments, the compound isadministered within twelve hours after an injury, such as a TBI. In someembodiments, the compound is administered within 11 hours of a TBI,stroke or other injury to the brain, or within 10 hours, or within 9hours, or within 8 hours, or within 7 hours, or within 6 hours, orwithin 5 hours, or within 4 hours, or within 3 hours, such as within twoor one hour. In some embodiments, the compounds are administered withinone day (i.e. 24 hours) of the injury. In certain embodiments, thecompounds are provided to individuals at risk of a stroke, such as thosewho are suffering from atherosclerosis or have a family history of heartdisease. These compounds can be provided to individuals as apreventative therapy to decrease neural trauma.

In another embodiment, a method for decreasing ischemia following abrain injury is provided comprising administering an effective amount ofa compound disclosed herein. Although it is not intended thatembodiments of the disclosure work by any particular mechanism, it isbelieved that administering certain compound is a means to reduce oreliminate the inflammatory immune reactions that follow a CNS injury. Byreducing the inflammatory response, the compounds can substantiallyreduce brain swelling and reduce the amount of neurotoxic substances(e.g., free radicals and excitotoxins) that are released from the siteof injury.

In certain embodiments, the concentration of the compound or salt, esteror prodrug thereof, is effective in the treatment or prevention oftypical neuronal damage that follows either a traumatic, ischemic orhemorrhagic injury to the CNS and hence, elicits a neuroprotectiveeffect. The therapeutically effective amount will depend on many factorsincluding, for example, the specific activity of the compoundadministered, the type of injury, the severity and pattern of theinjury, the resulting neuronal damage, the responsiveness of thepatient, the weight of the patient along with other intrapersonvariability, the method of administration, and the formulation used.

It is recognized that a traumatic injury to the CNS results in multiplephysiological events that impact the extent and rate ofneurodegeneration, and thus the final clinical outcome of the injury.The treatment of a traumatic injury to the CNS encompasses any reductionand/or prevention in one or more of the various physiological eventsthat follow the initial impact. For example, cerebral edema frequentlydevelops following a traumatic injury to the CNS and is a leading causeof death and disability. Cortical contusions, for example, producemassive increases in brain tissue water content which, in turn, cancause increased intracranial pressure leading to reduced cerebral bloodflow and additional neuronal loss. Hence, the methods disclosed hereinfind use in reducing and/or eliminating cerebral edema and/or reducingthe duration of the edemic event following a traumatic injury to theCNS. Assays to determine a reduction in edema are known in the art andinclude, but are not limited to, a decrease in tissue water contentfollowing the administration of the progestin or the progestinmetabolite (Betz et al. (1990) Stroke 21: 1199-204, which is hereinincorporated by reference). Furthermore, an overall improvement inbehavioral recovery can also be used as a measure for a decrease inedema. A decrease in edema in the effected tissue by at least about 15%to 30%, about 30% to 45%, about 45% to 60%, about 60% to 80%, or about80% to 95% or greater will be therapeutically beneficial, as will anyreduction in the duration of the edemic event.

Further physiological effects of brain injury include an inflammatoryresponse. In particular, some studies indicate that the acuteinflammatory response contributes significantly to injury after ischemia(see Perera, et al. (2005) Inflammation following stroke. J. CHn.Neurosc. 13:1-8; Barone and Feuerstein (1999) Inflammatory mediators andstroke: new opportunities for novel therapeutics). The stroke processtriggers an inflammatory reaction that may last up to several months.Suppression of inflammation can reduce infarct volume and improveclinical outcomes even with the initiation of therapy after 3 hours ofonset of stroke. In addition, an immune response can be triggered bothby strokes. Infiltrating leukocytes are thought to contribute tosecondary ischemic damage by producing toxic substances that kill braincells and disrupt the blood-brain barrier (see del Zoppo, et al. (2000)Advances in the vascular pathophysiology of ischemic stroke. Thromb Res.98:73-81) Infiltration occurs when leukocytes bind endothelialintercellular adhesion molecule-1 (ICAM-I) and ICAM-I is upregulatedafter ischemia.

TBI also elicits inflammatory, and in particular an immune responses.See, for example, Soares et al. (1995) J. Neurosci. 15:8223-33; Holminet al. (1995) Acta Neurochir. 132:110-9; Arvin et al. (1996) Neurosci.Biobehay. Rev. 20:445-52. Following a cortical impact, severeinflammatory reactions and gliosis at the impact site and at brain areasdistal to the primary site of injury occurs. The inflammatory responseis characterized by the expression of adhesion molecules on the vascularsurfaces, resulting in the adherence of immune cells and subsequentextravasation into the brain parenchyma. By releasing cytokines, theinvading macrophages and neutrophils stimulate reactive astrocytosis.Release of different chemokines by other cell types induces these immunecells to become phagocytic, with the simultaneous release of freeradicals and pro-inflammatory compounds, e.g., cytokines,prostaglandins, and excitotoxins (Arvin et al. (1996) Neurosci.Biobehay. Ref 20:445-52; Raivich et al. (1996) Kelo J. Med. 45:239-47;Mattson et al. (1997) Brain Res. Rev. 23:47-61; all of which are hereinincorporated by reference).

Assays for assessing the efficacy of the compounds described hereininclude assays to determine a decrease in an ischemic event include, forexample, a decrease in infarct area, improved body weight, and improvedneurological outcome. Assays to measure a reduction in lipidperoxidation in both brain homogenate and in mitochondria are known inthe art and include, for example, the thiobarbituric acid method (Roofet al. (1997) MoI. Chem. Neuropathol. 31: 1-11; Subramanian et al.(1993) Neurosci. Lett. 155:151-4; Goodman et al. (1996) J. Neurochem.66:1836-44; Vedder et al. (1999) J. Neurochem. 72:2531-8; all of whichare herein incorporated by reference) and various in vitro free radicalgenerating systems. Furthermore, alterations in the levels of criticalfree radical scavenger enzymes, such as mitochondrial glutathione can beassayed. See, for example, Subramanian et al. (1993) Neurosci. Lett.155:151-4; and Vedder et al. (1999) J. Neurochem. 72:2531-8; both ofwhich are herein incorporated by reference.

Methods to quantify the extent of central nervous system damage (i.e.,neurodegeneration) and to determine if neuronal damage was treated orprevented following the administration of a progesterone or compounddisclosed herein are well known in the art. Such neuroprotective effectscan be assayed at various levels, including, for example, by promotingbehavioral and morphological (i.e., enhancing tissue viability) recoveryafter traumatic brain injury. A variety of anatomical,immunocytochemical and immunological assays to determine the effect ofthe progestin metabolite on necrosis, apoptosis, and neuronal glialrepair are known in the art. As such, the neuroprotection will typicallyresult in at least about a 10% to 20%, 20% to 30%, 30% to 40%, 40% to60%, 60% to 80% or greater increase in neuronal survival and/orbehavioral recovery as compared to the control groups.

Histological and molecular marker assays for an increase in neuronalsurvival are known. For example, Growth Associated Protein 43 (GAP-43)can be used as a marker for new axonal growth following a CNS insult.See, for example, Stroemer et al. (1995) Stroke 26:2135-2144, Vaudano etal. (1995) J. of Neurosci 15:3594-3611. Other histological markers caninclude a decrease in astrogliosis and microgliosis. Alternatively, adelay in cellular death can be assayed using TUNEL labeling in injuredtissue. Further anatomical measures that can be used to determine anincrease in neuroprotection include counting specific neuronal celltypes to determine if the progestin or the progestin metabolite ispreferentially preserving a particular cell type (e.g., cholinergiccells) or neurons in general.

In addition, behavioral assays can be used to determine the rate andextent of behavior recovery in response to the treatment. Improvedpatient motor skills, spatial learning performance, cognitive function,sensory perception, speech and/or a decrease in the propensity toseizure may also be used to measure the neuroprotective effect. Suchfunctional/behavioral tests used to assess sensorimortor and reflexfunction are described in, for example, Bederson et al. (1986) Stroke17:472-476, DeRyck et al. (1992) Brain Res. 573:44-60, Markgraf et al.(1992) Brain Res. 575:238-246, Alexis et al. (1995) Stroke 26:2336-2346;all of which are herein incorporated by reference. Enhancement ofneuronal survival may also be measured using the Scandinavian StrokeScale (SSS) or the Barthl Index. Behavioral recovery can be furtherassessed using the recommendations of the Subcommittee of the NIH/NINDSHead Injury Centers in Humans (Hannay et al. (1996) J. Head TraumaRehabil. 11:41-50), herein incorporated by reference. Behavioralrecovery can be further assessed using the methods described in, forexample, Beaumont et al. (1999) Neural Res. 21:742-754; Becker et al.(1980) Brain Res. 200:07-320; Buresov et al. (1983) Techniques and BasicExperiments for the Study of Brain and Behavior; Kline et al. (1994)Pharmacol. Biochem. Behav. 48:773-779; Lindner et al. (1998) J.Neurotrauma 15:199-216; Morris (1984) J. Neurosci. Methods 11:47-60;Schallert et al. (1983) Pharmacol. Biochem. Behav. 18:753-759.

Assays that can be used to determine if a compound is imparting ananti-inflammatory and a nonspecific suppressive effect on the immunesystem following a traumatic CNS injury include, for example, areduction in cytokine induced microglial proliferation in vitro (Hoffmanet al. (1994) J. Neurotrauma 11:417-31; Garcia-Estrada et al. (1993)Brain Res. 628:271-8; both of which are herein incorporated byreference); a reduction in the generation of cytotoxic free radicals byactivated macrophages (Chao et al. (1994) Am. J. Reprod. Immunol.32:43-52; Robert et al. (1997) Nitric Oxide 1:453-62; Kelly et al.(1997) Biochem. Biophys. Res. Commun. 239:557-61; Ganter et al. (1992)J. Neurosci. Res. 33:218-30; all of which are herein incorporated byreference); a reduction in the expression of inducible nitric oxidesynthetase and the amount of nitric oxide release by macrophages (Robertet al. (1997) Nitric Oxide 1:453-62; Miller et al. (1996) J. Leukoc.Biol. 59:442-50; both of which are herein incorporated by reference);the release of a “progesterone-induced blocking factor” that inhibitsnatural killer cell activity (Cheek et al. (1997) Am. J. Reprod.Immunol. 37:17-20; Szekeres-Bartho et al. (1997) Cell Immunol.177:194-9; Szekeres-Bartho et al. (1996) Am. J. Reprod. Immunol.35:348-51; all of which are herein incorporated by reference); adecrease in the number of GF AP-positive astrocytes after brain injurywhich is suggestive of less secondary damage (Garcia-Estrada et al.(1993) Brain Res. 628:271-8; Garcie-Estrada et al. (1999) Int. J. Dev.Neurosci. 17:145-51; Cheek et al. (1997) Am. J. Reprod. Immunol.37:17-20; Szekeres-Bartho et al. (1997) Cell Immunol. 177:194-9;Szekeres-Bartho et al. (1996) Am. J. Reprod. Immunol. 35:348-51; all ofwhich are herein incorporated by reference); a reduction in the numberof inflammatory immune cells (OX42-positive cells); a reduction in theloss of ChAT-positive and COX-positive neurons; a reduction in thenumber of TUNEL-positive and MnSOD-positive neurons; and an increase inthe intensity of succinate dehydrogenase and cytochrome oxidaseactivity.

Furthermore, a reduction in the inflammatory immune reactions followinga traumatic brain injury can be assayed by measuring the cytokines levelfollowing the injury in the sham controls versus the progestin treatedsubjects. Cytokines are mediators of inflammation and are released inhigh concentrations after brain injury. The level of pro-inflammatorycytokines (e.g., interleukin 1-beta, tumor necrosis factor, andinterleukin 6) and the level of anti-inflammatory cytokines (e.g.,interleukin 10 and transforming growth factor-beta) can be measured. Forinstance, “real-time” polymerase chain reactions (PCR) can be used tomeasure the strength of the mRNA signal and ELISA can be used todetermine protein levels. In addition, histological analysis fordifferent inflammatory cell types (e.g., reactive astrocytes,macrophages and microglia) can be used to measure a reduction in theinflammatory response.

The compounds disclosed herein can also have potential for use in otherdisorders including multiple sclerosis, catamenial epilepsy, diabeticneuropathy, inflammatory disorders (e.g., rheumatoid arthritis,inflammatory bowel disease), hemorrhagic shock, Niemann-Pick disorder,cerebral palsy, and congenital heart disorders.

In specific embodiments, the disclosure relates to a method of treatmentor prevention of neural degeneration related to Amyotrophic LateralSclerosis (ALS) comprising administering a compound described herein, ora pharmaceutically acceptable salt, ester or prodrug thereof, to apatient suffering from or at risk of suffering from ALS. ALS, morecommonly known as Lou Gehrig's Disease, strikes both males and females,typically between the ages of 40 and 70. This is a motor neuron disorderin which both the upper and lower motor neurons are affected. Patients'muscles atrophy as the motor neurons cease sending signals to initiatemovement. This affects not only muscles required for locomotion but alsothe muscles used in swallowing. Life expectancy post-diagnosis is 2-5years. The cause of ALS is uncertain, but excitotoxicity, inflammation,oxidative stress and protein aggregation have been shown. In some cases,super oxide dismutase 1 (SODl) has been determined to be aberrant.Glutamate toxicity is now generally accepted as part of AS pathology.Progesterone has proven to protect neurons from the effects of thistoxicity. The only compound approved for the treatment of ALS isRilutek™ which may reduce glutamate levels. It is not curative but hasreduced the rate of progression in some patients.

In another specific embodiment, the disclosure relates to a method oftreatment or prevention of neural degeneration related to Parkinson'sDisease (PD) comprising administering a compound described herein, or apharmaceutically acceptable salt, ester or prodrug thereof, to a subjectsuffering from or at risk of suffering from PD. PD is aneurodegenerative disease of unknown etiology that results in theprogressive loss of nerve cell function in the brain. In PD, cells inthe substania nigra of the brain cease to function properly and die.These cells produce dopamine, a neurotransmitter. Dopamine regulatesthose parts of the brain which control the initiation of movement andcoordination. Without dopamine, a patient will begin to experiencetremors, bradykinesia, postural instability, rigidity of limbs andtrunk, and/or impaired balance and coordination. Not all patientsexperience all symptoms nor do they progress at the same rate.

In another embodiment, the disclosure relates to a method of treating orpreventing neural degeneration related to spinal cord trauma comprisingadministering a compound described herein, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, to a patient in need thereof.In another specific embodiment, a method of treatment or prevention ofneural degeneration related to hypoxia is provided comprisingadministering a steroid analog described herein, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, to a patient in need thereof.

Hormone Therapies

Within certain embodiments, the disclosure relates to using compoundsdisclosed herein for any therapies that progesterone is typicallyutilized such as hormonal therapies. In certain embodiments, compoundsdisclosed herein may be used to support pregnancy in AssistedReproductive Technology (ART) cycles such as In-vitro Fertilization(IVF). In vitro fertilization (IVF) is the technique of lettingfertilization of the male and female gametes (sperm and egg) occuroutside the female body. Techniques usually used in in vitrofertilization include transvaginal ovum retrieval and embryo transfer.Transvaginal ovum retrieval is a process whereby a needle is insertedthrough the back of the vagina and guided via ultrasound into theovarian follicles to collect the fluid that contains the eggs. Embryotransfer is the step in the process whereby one or several embryos areplaced into the uterus of the female with the intent to establish apregnancy. Compounds disclosed herein, optionally in combination withprogesterone, may be administered to the uterus to improve thelikelihood of pregnancy.

In certain embodiments, the disclosure relates to administeringcompounds disclosed herein to a subject in order to control persistentanovulatory bleeding, prepare uterine lining in infertility therapy, andto support early pregnancy. Patients with recurrent pregnancy loss dueto inadequate progesterone production may receive compounds disclosedherein optionally in combination with progesterone.

In certain embodiments, the discloser relates to administering compoundsdisclosed herein for preventing preterm birth in women at risk forpreterm birth. In certain embodiments, the subject is a women with ashort cervix. In certain embodiments, the compounds are administeredafter pregnancy or 3, 4, 5, 6, 7, or 8 months after conception up untilbirth.

In certain embodiments, the disclosure relates to methods of treating orpreventing endometrial hyperplasia comprising administering an effectiveamount of a compound or a pharmaceutical composition comprising acompound disclosed herein to a subject in need thereof. In certainembodiments, the subject is a non-hysterectomized postmenopausal women.In certain embodiments, the pharmaceutical composition is administeredin combination with estrogen.

In certain embodiments, the disclosure relates to methods of treating orpreventing secondary amenorrhoea comprising administering a compound ora pharmaceutical composition comprising a compound disclosed herein to asubject in need thereof.

In certain embodiments, the disclosure relates to methods of providingimmunosuppression comprising administering an effective amount of acompound or a compound or a pharmaceutical composition comprising acompound disclosed herein to a subject in need thereof. In certainembodiments, the subject is the recipient of an organ transplant. Incertain embodiments, the pharmaceutical composition is administered incombination with a second immunosuppressive agent.

EXPERIMENTAL Example 1: Synthesis of Compounds(E)-(((1-(10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylidene)amino)oxy)methylDihydrogen Phosphate [EPRX-01723]

The preparation of this compound is illustrated in FIG. 3.3β-Hydroxypregn-5-en-20-one is condensed withO-((methylthio)methyl)hydroxylamine to give the oxime compound as asingle oxime isomer (E). Standard Oppenauer oxidation conditions producethe ketone oxime compound. Displacement of the methylthio group with thephosphate group is accomplished with phosphoric acid in the presence ofN-iodosuccinimide, followed by conversion to the disodium salt andpurification by reverse-phase column chromatography, gives EPRX-01723.

(((E)-(17-acetyl-10,13-dimethyl-7,8,9,11,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H,6H, 10H)-ylidene)amino)oxy)methyl Dihydrogen Phosphate [EPRX-01619]

The preparation of this compound is illustrated in FIG. 4. Selectiveprotection of progesterone at the C-20 ketone is accomplished inethylene glycol in the presence of an acid catalyst. Condensation withO-((methylthio)methyl)hydroxylamine gives two geometric oxime isomerswhich are separated from each other to provide the E configuration.Ketal deprotection is accomplished with an acid catalyst. Displacementof the methylthio group with the phosphate group is accomplished withphosphoric acid in the presence of N-iodosuccinimide, followed byconversion to the disodium salt and purification by reverse-phase columnchromatography, gives EPRX-01619.

1-((8S,9S,10R,13S,14S,17S,E)-3-(Hydroxyimino)-10,13-dimethyl-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone(2)

A round bottom flask was charged with solid(8S,9S,10R,13S,14S,17S,E)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-oneoxime (1.00 g, 2.68 mmol) and dissolved in acetone (150 mL) at ambienttemperature under nitrogen. See MacNevin et al., J. Med. Chem., 2009, 52(19), 6012-6023, hereby incorporated by reference. p-Toluenesulfonicacid monohydrate (0.102 g, 0.54 mmol) was added, and the mixture wasstirred at ambient temperature 2.5 h. The mixture was concentrated byrotary evaporation, and the residue was purified by flash chromatography(0-20% EtOAc in hexanes) to afford 2 (0.30 g, 34% yield) as a whitesolid.

tert-Butyl (5)-1-((E)-((8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-7,8,9,11-tetrahydro-1H-cyclopenta[a]phenanthren-3(2H, 6H,10H,12H,13H,14H,15H,16H,17H)-ylidene)aminooxy)-3-methyl-1-oxobutan-2-ylcarbamate(51)

A round bottom flask was charged with solid 2 (2.6 g, 7.89 mmol) anddichloromethane (30 mL) under nitrogen with stirring. Solid L-Boc-Val-OH(3.43 g, 15.8 mmol) was added all at once to the solution, followed byDMAP (0.096 g, 0.79 mmol), and DIPEA (2.75 mL, 15.8 mmol) was addeddropwise via syringe. EDCI (3.03 g, 15.8 mmol) was added in one portion,the reaction mixture was allowed to slowly come to room temperature, andwas stirred at ambient temperature for 18 h. Saturated aqueous sodiumbicarbonate (50 mL) was added, the organic layer was removed, and theaqueous layer was extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed sequentially with water (3×50 mL) and brine(3×50 mL), dried over sodium sulfate, filtered, and concentrated underreduced pressure. The yellow oil was purified by flash chromatography(10-30% EtOAc in hexanes) to afford S1 (3.80 g, 91%) as a white solid.

(S)-1-((E)-((8S,9S,10R,13S,14S,17S)-17-Acetyl-10,13-dimethyl-7,8,9,11-tetrahydro-IH-cyclopenta[a]phenanthren-3(2H,6H,10H,12H,13H,14H,15H,16H,17H)-ylidene)aminooxy)-2-amino-3-methylbutan-1-oneHydrochloride (1)

A round bottom flask was charged with solid Si (2.20 g, 4.16 mmol), 13mL of dichloromethane was added, and the stirred solution was cooled to0° C. under nitrogen using an ice bath. TFA (13 mL, 169 mmol) was slowlyadded over a 15 minute period, and stirring was continued at 0° C. untilreaction was complete, about 1 h. The mixture was concentrated underreduced pressure at <20° C. and the resulting light pink oil was driedin vacuo for 1 h. Dioxane (3 mL) was added to the residue and cooled to0° C. using an ice bath; 4.0 M HCl-dioxane solution was added dropwise(1.56 mL, 6.24 mmol) and stirring was continued at 0° C. for anadditional 30 minutes. Ether (50 mL) was added, the mixture was stirredat 0° C. for 15 minutes, and the supernatant was decanted from the whitesolid. The solid was triturated with additional ether (3×50 mL) anddried in vacuo to afford 1 (1.50 g, 78% yield) as a white solid, mp159-161° C.

(E)-14(3S,8S,9S,10R,13S,14S,17S)-3-Hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanoneoxime (S2). See. Vasil'tov et al., Chemistry of Heterocyclic Compounds,2001, 37(12), 1488-1492 and Kim et al., Molecules, 2009, 14, 4655-4668.

A round bottom flask was charged with 5-pregnen-3β-ol-20-one (20.6 g,65.1 mmol) and methanol (500 mL), and the mixture was heated to refluxwith stirring to dissolve all solids. Hydroxylamine hydrochloride (9.05g, 130 mmol) and sodium acetate (11.75 g, 143 mmol) were dissolved inwater (30 mL), and this solution was added to the solution over 3 h.After addition was complete, the mixture was refluxed for an additional3 h; a white precipitate formed during this time. The mixture was cooledto ambient temperature, water (300 mL) was added, and the resultingmixture was stirred for 45 minutes. The solids were collected by vacuumfiltration, washed with additional water (3×300 mL), and dried in vacuoto afford S2 (21.0 g, 97% yield) as a white solid, mp 210° C. (dec.).Spectral data agreed with that previously reported in the literature: ¹HNMR (400 MHz, CDCl₃) δ: 8.05 (br s, 1H), 5.41-5.31 (m, 1H), 3.54 (welldefined multiplet centered at 3.54, 1H), 2.34-2.19 (m, 2H), 2.14-1.98(m, 2H), 1.94-1.82 (m, 1H), 1.90 (s, 3H), 1.75-1.42 (m, 10H), 1.35-0.95(m, 6H), 1.02 (s, 3H), 0.65 (s, 3H).

(8 S,9S,10R,13 S,14S,17S)-17-((E)-1-(Hydroxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (3)

A round bottom flask fitted with a reflux condenser and Dean-Stark trapwas charged with solid S2 (21.0 g, 63.3 mmol), N-methylpiperidone (73.1ml, 633 mmol), and toluene (500 mL). The resulting mixture was heated toreflux for 2 h for azeotropic removal of adventitious water. Aluminumisopropoxide (25.9 g, 127 mmol) was slowly added to the clear solution,and the resulting mixture was refluxed for 18 h. The dark orange mixturewas cooled to ambient temperature, and a saturated aqueous Rochelle saltsolution (300 mL) was slowly added over 30 min with stirring. Afterfurther stirring for 45 min, the layers were separated, and the aqueouslayer was extracted with dichloromethane (3×200 mL). The combinedorganic layers were washed with water (3×150 mL) and brine (1×100 mL),dried over sodium sulfate, filtered, and concentrated by rotaryevaporation. The dark orange oil was taken up in 50% EtOAc/DCM andpassed through a plug of silica gel, eluting with 1 L of 50% EtOAc/DCM.The filtrate was concentrated under reduced pressure and purified bysilica gel chromatography (5-20% EtOAc in DCM) to afford 3 (16.0 g, 77%yield) as a white solid.

(E)-1-((3 S,8S,9S,10R,13 S,14 S,17S)-3-Hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanoneO-methyl Oxime (S3)

A round bottom flask fitted with a reflux condenser was charged with5-pregnen-30-ol-20-one (3.16 g, 10.0 mmol), methoxylamine hydrochloride(0.92 g, 11.0 mmol) and pyridine (10 mL). The mixture was heated to 95°C. for 3 h, cooled to room temperature, and poured into water (100 mL).The white solid was collected by vacuum filtration, washed with water(3×100 mL), and dried in vacuo. The crude solid was purified by flashchromatography (85:15 CH₂Cl₂:EtOAc) to afford S3 (2.75 g, 87% yield) asa white solid.

(8 S,9 S, 10R,13 S,14S,17S)-17-((E)-1-(Methoxyimino)ethyl)-10,13-dimethyl-11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (4)

A round bottom flask fitted with a Dean-Stark trap and a refluxcondenser was charged with S3 (1.73 g, 5.00 mmol), N-methyl-4-piperidone(5.66 g, 50 mmol) and toluene (50 mL). The mixture was refluxed for 1 hfor azeotropic removal of adventitious water, was cooled to ambienttemperature, and aluminum isopropoxide (2.04 g, 10 mmol) was added inone portion. The mixture was refluxed for 18 h, cooled to ambienttemperature, and treated by stirring with saturated aqueous Rochellesalt solution (25 mL) for 2 h. The layers were separated, and theaqueous layer was extracted with DCM (3×25 mL). The combined organiclayers were washed with water (3×50 mL) and brine (3×50 mL), dried overNa₂SO₄, filtered, and concentrated by rotary evaporation. The crudeorange solid was purified by flash chromatography (3:1 hexanes:EtOAc) toafford 4 (1.06 g, 62% yield) as a white solid.

(E)-1-((3 S,8S,9S,10R,13 S,14 S,17S)-3-Hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanoneO-2-morpholinoethyl Oxime (S4): See Courtney et al., WO 2008142720 andChen et al., WO 2009097578

A round bottom flask was charged with O-(2-morpholinoethyl)hydroxylaminedihydrochloride (1.97 g, 9.0 mmol), sodium acetate (1.60 g, 19.5 mmol),and 5-pregnen-3β-ol-20-one (2.37 g, 7.5 mmol). The flask was fitted witha reflux condenser, and MeOH (40 mL) was added along with water (4 mL).The mixture was refluxed with stirring for 16 h. The reaction mixturewas cooled to ambient temperature and was partitioned between saturatedaqueous NaHCO₃ (100 mL) and dichloromethane (150 mL). The aqueous layerwas extracted with additional DCM (2×150 mL), and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated by rotaryevaporation. The crude solid was purified by flash chromatography usinga CombiFlash (80 g column, 2 to 10% EtOH in EtOAc) to afford S4 (2.79 g,84% yield) as a white, flaky solid.

(8S,9S,10R,13S,14S,17S)-10,13-Dimethyl-17-((E)-1-(2-morpholinoethoxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one(5)

A round bottom flask fitted with a reflux condenser and Dean-Stark trapwas charged with S4 (1.56 g, 3.50 mmol), N-methyl-4-piperidone (3.96 g,35 mmol), and toluene (30 mL). The mixture was refluxed for 1 h forazeotropic removal of adventitious water, and recooled to roomtemperature. Aluminum isopropoxide (1.43 g, 7.0 mmol) was added all atonce, and the mixture was returned to reflux with stirring. Afterrefluxing 20 h, the mixture was cooled to ambient temperature and wastreated with saturated aqueous Rochelle salt solution (50 mL) bystirring for 2 h. The mixture was extracted with DCM (3×100 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated by rotary evaporation. The crude orange oil was purified byflash chromatography using a CombiFlash (80 g column, 1 to 10% EtOH inEtOAc) to afford 5 (1.21 g, 78% yield) as a white solid.

(8 S,9S,10R,13S,14S,17S)-17-((E)-1-(acetoxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one(6)

A round bottom flask was charged with 3 (0.82 g, 2.5 mmol) and pyridine(5 mL) under nitrogen with stirring at room temperature. Aceticanhydride (1.7 mL, 18.0 mmol) was added all at once via syringe,followed by DMAP (0.050 g, 0.40 mmol). The mixture was stirred for 18 hat ambient temperature, then diluted with dichloromethane (50 mL),washed with saturated aqueous NH₄Cl (3×50 mL) and brine (1×50 mL), driedover Na₂SO₄, filtered, and concentrated by rotary evaporation. Theresidue was purified by flash chromatography using a Combiflash (25 gcolumn, 1 to 10% EtOAc in DCM) to afford 6 (0.71 g, 76% yield) as awhite solid.

tert-Butyl (S)-1-((E)-1-((8S,9S,10R,13 S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylideneaminooxy)-3-methyl-1-oxobutan-2-ylcarbamate(S5)

A round bottom flask was charged with 3 (3.29 g, 10.0 mmol),L-Boc-Val-OH (4.34 g, 20.0 mmol), DMAP (0.122 g, 1.00 mmol), anddichloromethane (50 mL) under nitrogen at 0° C. To the stirred solutionwas added N,N-diisopropylethylamine (3.48 mL, 20.0 mmol) all at once viasyringe, followed by EDCI (3.83 g, 20.0 mmol) in one portion, and theresulting mixture was stirred for 18 h at ambient temperature. Saturatedaqueous NH₄Cl (100 mL) was added, the organic layer was removed, and theaqueous layer was extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with brine (1×50 mL), dried over Na₂SO₄,filtered, and concentrated by rotary evaporation. Purification by flashchromatography (3:2 hexanes:EtOAc) afforded S5 (4.87 g, 92%) as a whitesolid.

(8 S,9S,10R,13S,14S,17S)-17-((E)-1-((S)-2-Amino-3-methylbutanoyloxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-oneHydrochloride (7)

Solid S5 (1.06 g, 2.0 mmol) was dissolved in dichloromethane (6 mL) at0° C. under nitrogen with stirring. TFA (6 mL) was added dropwise viasyringe with stirring, and the mixture was stirred at 0° C. for 90 min.The volatiles were removed by rotary evaporation, and the residue wasdried in vacuo for 2 h. The resulting brown oil was cooled to 0° C. withstirring under nitrogen, and a solution of 4.0 M HCl in dioxane (0.60mL, 2.4 mmol) was added dropwise via syringe. The mixture was stirred 5minutes, then Et₂O (20 mL) was added. The resulting mixture was warmedto ambient temperature, stirred for 20 minutes, and collected by vacuumfiltration. The solids were washed with additional Et₂O (2×20 mL) anddried in vacuo to afford 7 (0.91 g, 95% yield) as a white solid.

(S)-tert-Butyl2-(((E)-1-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylideneaminooxy)carbonyl)pyrrolidine-1-carboxylate(S6)

A round bottom flask was charged with 3 (0.659 g, 2.00 mmol),L-Boc-Pro-OH (0.861 g, 4.00 mmol), DMAP (0.024 g, 0.20 mmol), anddichloromethane (20 mL) under nitrogen at 0° C. To the stirred solutionwas added N,N-diisopropylethylamine (0.697 mL, 4.00 mmol) all at oncevia syringe, followed by EDCI (0.767 g, 4.00 mmol) in one portion, andthe resulting mixture was stirred for 18 h at ambient temperature.Saturated aqueous NH₄Cl (20 mL) was added, the organic layer wasremoved, and the aqueous layer was extracted with dichloromethane (3×20mL). The combined organic layers were washed with brine (1×40 mL), driedover Na₂SO₄, filtered, and concentrated by rotary evaporation.Purification using the Combiflash (40 g column, 10 to 50% EtOAc inhexanes) afforded S6 (0.974 g, 92%) as a white solid.

(8 S,9S,10R,13 S,14S,17S)-10,13-Dimethyl-174(E)-1-((S)-pyrrolidine-2-carbonyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-onehydrochloride (8)

A round bottom flask was charged with S6 (0.53 g, 1.00 mmol) anddichloromethane (3 mL), and the stirred solution was cooled to 0° C.under nitrogen. Trifluoroacetic acid (4.56 g, 40 mmol) was slowly addedvia syringe, and the solution was stirred 2 h at 0° C. Volatiles wereremoved by rotary evaporation (bath temperature<10° C.) and driedfurther in vacuo. The residue was treated with a 4.0 M dioxane solutionof HCl in dioxane (1.2 mmol, 0.30 mL) at 0° C. and stirred for 15 min.Ether (25 mL) was added, and stirring continued for an additional 15 minat ambient temperature. The supernatant was decanted, and the solid wastriturated with ether (3×25 mL). The solid was dried in vacuo to afford8 (0.40 g, 87% yield) as a white solid

(8 S,9S,10R,13S,14S,17S)-10,13-Dimethyl-174(E)-14S)-1,1-Dimethylpyrrolidine-2-carbonyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-oneiodide (9)

See Han et al., Eur. J. Org. Chem., 2005, 5, 934-938.

A round bottom flask was charged with solid 3 (0.99 g, 3.0 mmol),N-methyl-L-proline5 (0.78 g, 6.0 mmol), (0.04 g, 0.30 mmol), anddichloromethane (30 mL) under nitrogen. The stirred mixture was cooledto 0° C., and N,N-diisopropylethylamine (1.05 mL, 6.0 mmol) was addedvia syringe. Solid EDCI (1.15 g, 6.0 mmol) was added in one portion, andthe mixture was stirred at ambient temperature for 18 h. Saturatedaqueous NaHCO₃(30 mL) was added, and the organic layer was removed. Theaqueous layer was extracted with dichloromethane (3×30 mL) and thecombined organic layers were washed with brine (1×30 mL), dried overNa₂SO₄, filtered, and concentrated by rotary evaporation. The residuewas purified by flash chromatography using a Combiflash (40 g column, 0to 100% EtOAc in DCM) to afford 1.1 g of desired coupling product in 90%purity as determined by 1H NMR. A second attempt at purification byadditional chromatography resulted in further degradation (0.56 g crude,80% pure), and the material was used as-is for the next step.

A round bottom flask was charged with the 0.56 g of crude material fromthe previous step, methyl iodide (0.63 mL, 10.1 mmol), and acetone (20mL). The mixture was refluxed under nitrogen for 2 h, during which timea white solid precipitated. After cooling to ambient temperature, thesolid was collected by vacuum filtration, washed with additional acetone(2×20 mL), and dried in vacuo to afford 9 (0.45 g, 25% over 2 steps) asa white solid

(8 S,9S,10R,13S,14S,17S)-17-((E)-1-(2-(Dimethylamino)acetoxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one(10)

A round bottom flask was charged with 3 (0.66 g, 2.0 mmol) anddichloromethane (20 mL), and the stirred solution was cooled to 0° C.under nitrogen. N,N-Dimethylglycine (0.52 g, 5.0 mmol), DMAP (0.073 g,0.60 mmol), and N,N-diisopropylethylamine (0.87 mL, 5.0 mmol) were addedto the solution. EDCI (0.96 g, 5.0 mmol) was added in one portion, themixture was warmed to ambient temperature, and was stirred for 18 h.Saturated aqueous NaHCO₃(20 mL) was added, the layers were separated,and the aqueous layer was extracted with dichloromethane (2×20 mL). Thecombined organic layers were washed with brine (1×40 mL), dried overNa₂SO₄, filtered, and concentrated by rotary evaporation. The crudeyellow oil was purified by flash chromatography using a Combiflash (40 gcolumn, 0 to 10% EtOH in EtOAc) to yield 10 (0.62 g, 73% yield) as awhite solid.

(8 S,9 S, 10R,13S,14S,17S)-17-((E)-1-(2-(triimethylamino)acetoxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-oneIodide (11)

A round bottom flask was charged with 10 (0.10 g, 0.25 mmol) and acetone(5 mL) under nitrogen with stirring. Iodomethane (0.16 mL, 2.50 mmol)was added, and the mixture was refluxed for 4 h; the solution turnedyellow and a precipitate formed after 5 min. The mixture was cooled toambient temperature and the supernatant was decanted. The solid wastriturated with acetone (2×10 mL) at 70° C. and dried in vacuo to yield11 (0.74 g, 53% yield) as a yellow solid.

(8 S,9S,10R,13S,14S,17S)-10,13-Dimethyl-17-((E)-1-(2-morpholinoacetoxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one(12)

See Fedi et al., J. Med. Chem. 2004, 47, 6935-6947.

A round bottom flask was charged with 3 (0.659 g, 2.00 mmol), DMAP(0.073 g, 0.60 mmol), 2-morpholinoacetic acid (1.30 g, 5.00 mmol) anddichloromethane (20 mL) with stirring under nitrogen at 0° C.N,N-Diisopropylethylamine (1.74 mL, 10.00 mmol) was added via syringe,followed by addition of EDCI (0.959 g, 5.00 mmol) in a single portion.The resulting solution was stirred at ambient temperature for 18 h. Themixture was poured into saturated aqueous NaHCO₃(20 mL) and the organiclayer was removed. The aqueous layer was extracted with dichloromethane(2×20 mL), and the combined organic layers were washed with brine (1×40mL), dried over Na₂SO₄, filtered, and concentrated by rotaryevaporation. The crude was purified using a Combiflash (80 g column, 0.5to 10% EtOH in EtOAc) to yield 12 (0.861 g, 94% yield) as an off-whitesolid.

(8 S,9S,10R,13 S,14S,17S)-10,13-Dimethyl-174(E)-1-(2-(4-methylpiperazin-1-yl)acetoxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (13)

A round bottom flask was charged with 3 (0.33 g, 1.0 mmol),2-(4-methylpiperazin-1-yl)acetic acid (0.32 g, 2.0 mmol), anddichloromethane (10 mL) under nitrogen with stirring. The solution wascooled to 0° C., and DMAP (0.012 g, 0.10 mmol) andN,N-diisopropylethylamine (0.35 mL, 2.0 mmol) were added, followed byaddition of EDCI (0.38 g, 2.0 mmol) in one portion. After stirring for16 h at ambient temperature, the mixture was poured into saturatedaqueous NaHCO₃(10 mL) and the organic layer was removed. The aqueouslayer was extracted with DCM (3×20 mL), and the combined organics werewashed with brine (1×40 mL), dried over Na₂SO₄, filtered, andconcentrated by rotary evaporation. The crude yellow oil was purifiedusing a Combiflash (40 g column, 0.5 to 10% MeOH in DCM) to afford 13(0.46 g, 98% yield) as a pale yellow oil that solidified upon standing.

(8 S,9 S, 10R,13 S,14S,17S)-10,13-Dimethyl-174(E)-1-(picolinoyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (14)

A round bottom flask was charged with 3 (0.66 g, 2.00 mmol), nicotinicacid (0.74 g, 6.00 mmol), and dichloromethane (20 mL) with stirringunder nitrogen. The solution was cooled to 0° C., and DMAP (0.073 g,0.60 mmol) and N,N-diisopropylethylamine (0.78 g, 6.00 mmol) were added,followed by EDCI (1.15 g, 6.00 mmol). After stirring for 16 h at ambienttemperature, the reaction was quenched by the addition of water (20 mL)and the organic layer was removed. The aqueous layer was extracted withdichloromethane (3×20 mL). The combined organic layers were washed withwater (3×20 mL) and brine (1×20 mL), dried over Na₂SO₄, filtered, andconcentrated by rotary evaporation. The dark orange oil was purifiedusing a Combiflash (40 g column, 0 to 30% EtOAc in DCM) to afford 14(0.70 g, 80% yield) as a white solid.

3-(((E)-1-((8S,9S,10R,13 S,14 S,17S)-10,13-Dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylideneaminooxy)carbonyl)-1-methylpyridiniumIodide (15)

A round bottom flask was charged with 14 (0.54 g, 1.25 mmol), acetone(25 mL), and iodomethane (0.78 mL, 12.5 mmol) under nitrogen. Themixture was refluxed for 5 h; the solution turned yellow and precipitateformed after 5 minutes. The mixture was cooled to ambient temperatureand the supernatant was decanted. The solid was triturated with acetone(3×50 mL) and dried in vacuo to yield 15 (0.52 g, 65% yield) as a brightyellow solid

tert-Butyl 4-(((E)-1-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylideneaminooxy)carbonyl)benzylcarbamate(S7)

See Erdelyi et al., Organic & Biomolecular Chemistry, 2008, 6(23),4356-4373.

A round bottom flask was charged with 3 (1.65 g, 5.0 mmol),4-(Boc-aminomethyl)benzoic acid (2.51 g, 10.0 mmol), and DMAP (0.122 g,1.000 mmol) in dichloromethane (50 mL) under nitrogen. The stirredsolution was cooled to 0° C. N,N-Diisopropylethylamine (1.74 mL, 10.0mmol) was added, followed by solid EDCI (1.92 g, 10.0 mmol) in oneportion. The mixture was slowly warmed to ambient temperature andstirred 18 h. The mixture was poured into saturated aqueous NaHCO₃(50mL) and the organic layer was removed. The aqueous layer was extractedwith dichloromethane (3×50 mL) and the combined organic layers weredried over Na₂SO₄, filtered, and concentrated by rotary evaporation. Theresidue was purified by flash chromatography using the CombiFlash (80 gcolumn, 1 to 15% EtOAc in hexanes) to afford S7 (2.6 g, 93% yield) as awhite solid.

(8 S,9 S, 10R,13S,14S,17S)-17-((E)-1-(4-(aminomethyl)benzoyloxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one(16)

A round bottom flask was charged with S7 (2.25 g, 4.00 mmol) anddichloromethane (12 mL) under nitrogen, and the stirred solution wascooled to 0° C. TFA (12 mL, 160 mmol) was added dropwise by syringe over10 min, and stirring was continued at 0° C. for 1 h. The volatiles wereremoved under reduced pressure and the residue was dried in vacuo. Thebrown oil was dissolved in THF (6 mL), the solution was cooled to 0° C.,and treated with a 4.0 M HCl-dioxane solution (1.25 mL, 5.0 mmol) over a10 minute period. The mixture was stirred an additional 30 minutes at 0°C., and ether (120 mL) was added, during which a white precipitateformed. The mixture was stirred an additional 15 min at 0° C., thesupernatant was decanted, and the solid was triturated twice with ether(2×120 mL) at 0° C. The solid was dried in vacuo to afford 16 (1.90 g,95% yield) as a white solid.

(8 S,9S,10R,13S,14S,17S)-10,13-dimethyl-174(E)-1-(4-((4-methylpiperazin-1-yl)methyl)benzoyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one(17)

See Seeliger et al., Cancer Research, 2009, 69(6), 2384-2392.

A round bottom flask was charged with 3 (0.66 g, 2.0 mmol),4-((4-methylpiperazin-1-yl)methyl)benzoic acid (1.27 g, 4.0 mmol), DMAP(0.049 g, 0.40 mmol), and dichloromethane (20 mL) under nitrogen withstirring. The mixture was cooled to 0° C. using an ice bath, andN,N-diisopropylethylamine (2.09 mL, 12.0 mmol) was added, followed bythe addition of solid EDCI (0.77 g, 4.0 mmol) in one portion. Themixture was slowly warmed to ambient temperature and stirred for 18 h.The mixture was poured into saturated aqueous NaHCO₃(20 mL), the organiclayer was removed, and the aqueous layer was extracted withdichloromethane (3×40 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated by rotary evaporation. The residuewas purified by flash chromatography using the CombiFlash (40 g column,1 to 10% MeOH in dichloromethane) to afford 17 (0.68 g, 62% yield) as awhite solid.

tert-Butyl 4-(((E)-1-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylideneaminooxy)carbonyl)piperidine-1-carboxylate(S8)

See Klein et al., J. Med. Chem. 1998, 41, 2492-2502.

A round bottom flask was charged with 3 (1.65 g, 5.00 mmol),1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 9 (2.29 g, 10.0mmol), DMAP (0.061 g, 0.50 mmol) and dichloromethane (50 mL) undernitrogen with stirring. The solution was cooled to 0° C., andN,N-diisopropylethylamine (1.742 ml, 10.00 mmol) was added via syringe.Solid EDCI (1.92 g, 10.0 mmol) was added in one portion and the solutionwas warmed to ambient temperature. After stirring for 18 h, saturatedaqueous NaHCO₃(50 mL) was added, the organic layer was removed, and theaqueous layer was extracted with dichloromethane (3×50 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated byrotary evaporation. The resulting oil was purified by flashchromatography using a CombiFlash (80 g column, 1 to 40% EtOAc in DCM)to afford S8 (2.57 g, 95% yield) as a white solid.

(8 S,9S,10R,13 S,14S,17S)-10,13-Dimethyl-174(E)-1-(piperidine-4-carbonyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one Hydrochloride (18)

A round bottom flask was charged with S8 (2.16 g, 4.0 mmol) anddichloromethane (12 mL) at 0° C. under nitrogen. TFA (12 mL, 160 mmol)was added dropwise via syringe to the stirred solution over 10 minutes,and the mixture was stirred an additional 1.5 hours at 0° C. Thevolatiles were removed by rotary evaporation, and the residue wasfurther dried in vacuo. The residue was dissolved in THF (6 mL), cooledto 0° C. under nitrogen with stirring, and treated with a 4.0 MHCl-dioxane solution (1.25 mL, 5.00 mmol). The mixture was stirred for30 minutes at 0° C., then ether (120 mL) was slowly added and stirringwas continued for an additional 15 minutes at 0° C., during which time awhite precipitate formed. The supernatant was decanted, and the solidwas triturated twice more with ether (2×120 mL) and dried in vacuo toafford 18 (1.84 g, 96% yield) as a white solid.

(8 S,9S,10R,13S,14S,17S)-10,13-Dimethyl-174(E)-1-(1-methylpiperidine-4-carbonyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one(19)

See Gray et al., J. Med. Chem., 1988, 31(4), 807-14.

A round bottom flask was charged with 3 (1.65 g, 5.00 mmol),1-methylpiperidine carboxylic acid hydrochloride (1.78 g, 10.0 mmol),DMAP (0.061 g, 0.50 mmol), and dichloromethane (100 mL) under nitrogenwith stirring. The mixture was cooled to 0° C., and DIPEA (1.74 mL, 10.0mmol) was added via syringe. Solid EDCI (1.92 g, 10.0 mmol) was added inone portion, the mixture was warmed to ambient temperature and stirred18 h. Saturated aqueous NaHCO₃(100 mL) was added, the organic layer wasremoved, and the aqueous layer was extracted with dichloromethane (3×100mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated by rotary evaporation. The residue was purified by flashchromatography using a Combiflash (80 g column, 1 to 10% MeOH in DCM) toafford 19 (1.68 g, 74% yield) as an off-white solid.

(8 S,9S,10R,13S,14S,17S)-10,13-Dimethyl-174(E)-1-(1,1-dimethylpiperidine-4-carbonyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-oneIodide (20)

A round bottom flask was charged with 19 (0.23 g, 0.50 mmol) and acetone(10 mL) at room temperature under nitrogen. To the stirred solution wasadded iodomethane (0.31 ml, 5.00 mmol) all at once via syringe, and themixture was heated to reflux with stirring for 1 h. A white precipitateformed during this time. The mixture was cooled to room temperature, thesupernatant was removed, and the solid was triturated with acetone (2×10mL). The solid was dried in vacuo to afford 20 (0.24 g, 80% yield) as awhite solid.

(R)-tert-Butyl3-(((E)-1-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylideneaminooxy)carbonyl)piperidine-1-carboxylate(S9)

Hauske, WO 201020889 and Hayashi et al., J. Med. Chem., 2009, 52 (3),610-625.

A round bottom flask was charged with 3 (0.99 g, 3.0 mmol),1-(tert-butoxycarbonyl)piperidine-3R-carboxylic acid (1.38 g, 6.00mmol), DMAP (0.037 g, 0.30 mmol) and dichloromethane (20 mL) undernitrogen with stirring. The mixture was cooled to 0° C., andN,N-diisopropylethylamine (1.05 mL, 6.00 mmol) was added via syringe,followed by solid EDCI (1.15 g, 6.00 mmol). The mixture was slowlywarmed to ambient temperature and stirred for 18 h. Saturated aqueousNH₄Cl (20 mL) was added, and the organic layer was removed. The aqueouslayer was extracted with dichloromethane (3×30 mL), and the combinedorganic layers were washed with brine (1×40 mL), dried over Na₂SO₄,filtered, and concentrated by rotary evaporation. The crude material waspurified using a Combiflash (80 g column, 1 to 20% EtOAc in DCM) toafford S9 (1.53 g, 94% yield) as a white, fluffy solid.

(8 S,9S,10R,13 S,14S,17S)-10,13-dimethyl-17-((E)-1-((R)-piperidine-3-carbonyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-onehydrochloride (21).

A round bottom flask was charged with S9 (1.40 g, 2.59 mmol) anddichloromethane (8.0 mL) under nitrogen, and the stirred solution wascooled to 0° C. The solution was treated with TFA (8.1 mL) dropwise viasyringe. The mixture was stirred for 1 h at 0° C., and volatiles wereremoved by rotary evaporation followed by high vacuum. The residue wastreated with a 4.0 M HCl-dioxane solution (0.81 mL, 3.24 mmol) dropwisevia syringe under nitrogen at 0° C., and the mixture was stirred for 15minutes. Ether (100 mL) was added and the mixture was stirred anadditional 20 minutes. The supernatant was removed, and the precipitatewas triturated twice with ether (2×100 mL). The solid was dried in vacuoto yield 1.11 g of 21(1.11 g, 90% yield) as a white powder.

(S)-tert-Butyl 3-(((E)-1-((8 S,9 S,10R,13 S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylideneaminooxy)carbonyl)piperidine-1-carboxylate(S10)

Prepared as above for S9 starting with1-(tert-butoxycarbonyl)piperidine-35-carboxylic acid to afford 1.52 g ofS10 (1.52 g, 94%) as a white, fluffy solid in 94% yield.

(8 S,9S,10R,13S,14S,17S)-10,13-Dimethyl-174(E)-14(S)-piperidine-3-carbonyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-onehydrochloride (22).

Prepared as above for 21 to afford 22 (1.07 g, 92% yield) as a whitesolid.

(E)-1-((3 S,8S,9S,10R,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanoneO-ethyl Oxime (511)

A round bottom flask was charged with 5-pregnen-3β-ol-20-one (3.16 g,10.0 mmol), O-ethylhydroxylamine hydochloride (1.07 g, 11.0 mmol), andpyridine (10 mL) under nitrogen. The stirred mixture was heated at 95°C. for 18 h, cooled to room temperature, poured into water (100 mL), andstirred for 15 min. The white solid was collected by filtration, washedwith water, and dried in vacuo. The solid was purified by flashchromatography (9:1 DCM:EtOAc) to afford S11 (3.49 g, 97% yield) as awhite solid.

(8 S,9 S,10R,13 S,14 S,17S)-17-((E)-1-(Ethoxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (S12)

A round bottom flask fitted with a reflux condenser and Dean-Stark trapwas charged with S11 (1.44 g, 4.00 mmol), N-methyl-4-piperidone (4.53 g,40 mmol) and toluene (40 mL) with stirring. The mixture was heated toreflux for 1 hr with azeotropic removal of adventitious water, recooledto ambient temperature, and aluminum isopropoxide (1.63 g, 8.00 mmol)was added all at once. After refluxing for 18 h, the mixture was cooledto ambient temperature and treated with a saturated solution ofRochelle's salt (20 mL) for 1 h. The organic layer was removed, and theaqueous layer was extracted with DCM (3×20 mL). The combined organiclayers were washed with water (3×20 mL) and brine (3×20 mL), dried overNa₂SO₄, filtered, and concentrated by rotary evaporation. The darkorange solid was purified by flash chromatography (4:1 hexanes:EtOAc) toafford S12 (0.83 g, 55% yield) as a white solid

(8 S,9 S, 10R,13 S,14S,17S)-17-((E)-1-(2-bromoethoxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (S13)

A round bottom flask was charged with 3 (1.97 g, 6.0 mmol) anddichloromethane (12 mL) with stirring. 1,2-dibromoethane (22.5 g, 120mmol) was added via syringe all at once, followed by solidtetrabutylammonium bromide (5.80 g, 18.0 mmol) in one portion, and 10%aqueous NaOH solution (24 mL) all at once. The mixture was stirred atambient temperature for 48 h, the organic layer was removed, and theaqueous layer was extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with brine (2×50 mL), dried over sodiumsulfate, filtered, and concentrated by rotary evaporation. The residuewas purified by silica gel chromatography (20:1 CH₂Cl₂/EtOAc) to affordS13 (1.32 g, 51% yield) as an off-white solid.

(8S,9S,10R,13S,14S,17S)-10,13-dimethyl-174(E)-1-(2-propylpentanoyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (S15)

A round bottom flask was charged with 3 (0.66 g, 2.00 mmol), valproicacid sodium salt (1.00 g, 6.00 mmol) and dichloromethane (20 mL) undernitrogen with stirring. To the solution was added DMAP (0.073 g, 0.60mmol) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol), followed bysolid EDCI (1.15 g, 6.00 mmol) in one portion. After stirring for 16 hat ambient temperature, the reaction was quenched by the addition ofwater (20 mL) and the organic layer was removed. The aqueous layer wasextracted with dichloromethane (3×20 mL). The combined organic layerswere washed with water (3×20 mL) and brine (1×20 mL), dried over Na₂SO₄,filtered, and concentrated by rotary evaporation. The residue waspurified using the Combiflash (0 to 30% EtOAc in DCM) to afford S15(0.73 g, 79% yield) as a white solid.

(8 S,9S,10R,13S,14S,17S)-10,13-Dimethyl-17-((E)-1-(4-(morpholinomethyl)benzoyloxyimino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one(S16)

See Moradei et al., WO 2005030704.

A round bottom flask was charged with 3 (0.66 g, 2.0 mmol),4-(morpholinomethyl)benzoic acid (0.89 g, 4.0 mmol), DMAP (0.049 g, 0.40mmol) and dichloromethane (50 mL) under nitrogen with stirring. Theresulting solution was cooled to 0° C., N,N-diisopropylethylamine (0.70mL, 4.0 mmol) was added, followed by solid EDCI (0.77 g, 4.0 mmol) inone portion. The mixture was warmed to ambient temperature and stirredfor 18 h. Saturated aqueous NaHCO₃(20 mL) was added, the organic layerwas removed, and the aqueous layer was extracted with dichloromethane(3×50 mL). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated by rotary evaporation. The residue was purified usingthe Combiflash (40 g column, 1 to 50% EtOAc in DCM) to afford S16 (1.01g, 95% yield) as a white solid.

General Procedure for Hydrolytic Stability Testing:

A small amount of the parent compound (0.1-0.3 mg/mL) was dissolved in10 mM pH 6.97 phosphate buffer, and the mixture was sonicated for 5 min.The solution was filtered through a 0.2 μM PES HPLC filter to removeinsoluble material. A sample was immediately analyzed by LCMS; this wastaken as t=0. The same filtered sample was kept at 23° C. and reinjectedat regular intervals without additional filtration or other samplepreparation. Insoluble oxime gradually precipitated, but this did notaffect the results. The area of the parent peak for each LC was measuredby automated integration. In each case, the baseline was flat withexcellent peak separation, peaks were well-defined, and only two peakswere seen (parent compound and oxime degradation product).

Pseudo first-order half-lives were calculated by determining the percentof parent compound remaining at each timepoint. Time (x-axis) wasplotted against the natural logarithm of the percent parent remaining(y-axis), the slope/intercept of the line was determined, and thefollowing equation was used:

t1/2=[ln(50)−y int]/slope

LC Conditions

Injection volume: 10 μL

Column temperature: 40° C.

Detector: 254 nm

Stationary Phase: Zorbax Eclipse XDB-C18 4.6×150 mm ID

Flow Rate: 1 mL/min

Mobile Phase: isocratic MeCN, pH 3 HCO₂H/HCO₂NH₄ buffer (see table forproportions used for each compound)

In Vitro Experiments

Primary cortical cells were seeded in multi-well plates and cultured for8 days before treatment. Cells were pre-treated with variousconcentrations of different PROG analogues (0.1, 1, 5, 10, 20, 40, 80μM) for 24 h. Then cells were then exposed to glutamate (0.5 μM) for thenext 24 h. The following two widely accepted cell death assays wereadopted for the evaluation of neuroprotective effect of various PROGanalogues.

MTT assay. Cytotoxicity was assessed by the MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay,which is based on the ability of a mitochondrial dehydrogenase enzymefrom viable cells to cleave the tetrazolium rings of the pale yellowMTT. This reaction forms dark blue formazan crystals which are largelyimpermeable to cell membranes, thus resulting in their accumulationwithin healthy cells. Solubilization of the cells results in theliberation of the crystals, which are then also solubilized. The numberof surviving cells is directly proportional to the level of the formazanproduct created. Concentrations were determined by photometric analysis.

LDH Release Assay. Cytotoxicity is assessed by measuring theintracellular lactate dehydrogenase (LDH) leakage in the medium by meansof a kinetic photometric assay. This is widely recognized as a cytotoxicend-point indicator for cell membrane disruption and viability. Thehigher the LDH activity, the higher the cell death.

Example 3: Cerebral Edema Assay Methods

Surgery—Contusions to the medio-frontal cortex (MFC) were created with apneumatic impactor device. Animals were anesthetized using isoflurane(5% induction, 2% maintenance, 700 mm N₂O, 300 mm O₂), and mounted in astereotaxic device with the head in a horizontal position. The body coretemperature was maintained with a homeothermic heating blanket system.Using a SurgiVet™ (model V3304) pulse oximeter, blood SpO₂ was monitoredand maintained at levels≥90%. Under aseptic conditions, a midlineincision was made in the scalp and the fascia retracted to expose thecranium. A centered, bilateral craniotomy was made 3 mm anterior tobregma using a 6 mm diameter trephan. After the removal of the bone, thetip of the impactor was moved to AP: 3.0; ML: 0.0, checked for adequateclearance, retracted to its elevated position, and lowered 3.5 mm DV.The contusion was then made at a velocity of 2.25 m/s with a braincontact time of 0.5 seconds. Following this procedure, the wound cavitywas thoroughly cleaned and all bleeding stopped before the fascia andscalp were sutured closed.

Progestin preparation and administration—Experimental treatments byinjection (progesterone and analogues) were made in stock solutionsusing 2-hydroxypropyl-P-cyclodextrin (HBC; 22.5% w/v solution in H₂O) asthe solvent. The HBC vehicle allows progesterone and analogues to bedissolved in a non-toxic, aqueous solution which can be administeredsafely by a variety of routes. The initial dose of progesterone oranalogue given at 1 h post-injury was delivered intraperitoneally (IP)for rapid absorption followed by a subcutaneous injection at 6 hpost-injury.

Edema measure—At 24 h post-injury, animals were given an IP overdose ofpentobarbital (75 mg/kg). The peri-contusional tissue samples from eacharea were assayed for water content as follows: samples were placed intopre-weighed containers, capped, and then immediately weighed to thenearest 0.0001 g. The containers were then uncapped and placed in avacuum oven and dried at 60° C., 0.3 atm for 24 h. The containers werethen recapped and reweighed to obtain the dry and wet-weightpercentages. A “% mean difference” value could then be calculated basedon the relative edema difference between injured and non-injured tissuesamples for a given animal.

While the disclosure has been described in detail with reference toexemplary embodiments, those skilled in the art will appreciate thatvarious modifications and substitutions may be made thereto withoutdeparting from the spirit and scope of the disclosure as set forth inthe appended claims. For example, elements and/or features of differentexemplary embodiments may be combined with each other and/or substitutedfor each other within the scope of this disclosure and appended claims.

1-15. (canceled)
 16. A compound selected from the group consisting ofFormula 1B and Formula 1C:

or esters, prodrugs, or salts thereof wherein Z is O or S; R¹ ishydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁴; R² is hydrogen, alkyl, halogen, nitro,cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl,alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl,alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, whereinR² is optionally substituted with one or more, the same or different,R⁴; or R¹ and R² form a carbocyclic ring; R³ is phosphate ion, hydrogen,—CH₂O(C═O)alkyl, or a group selected from alkyl, alkanoyl, and formylfurther substituted with one or more, the same or different, alkyl,amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl,wherein R³ is optionally substituted with one or more, the same ordifferent, R⁴; R^(3′) is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or agroup selected from alkyl, alkanoyl, and formyl further substituted withone or more, the same or different, alkyl, amino, hydroxyl, thiol,halogen, aryl, carbocyclyl, or heterocyclyl, wherein R^(3′) isoptionally substituted with one or more, the same or different, R⁴; R⁴is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R⁴ is optionally substituted with one ormore, the same or different, R⁵; and R⁵ is halogen, nitro, cyano,hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,carbamoyl, mercapto, sulfamoyl, methyl, ethyl, tertbutyl, methoxy,ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino,diethylamino, N-methyl-N-ethylamino, acetyl amino, N-methylcarbamoyl,N-ethylcarbamoyl, N,N-dim ethylcarbamoyl, N,N-di ethylcarbamoyl,N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl,ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl,N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethyl sulfamoyl, N,N-diethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl, carbocyclyl, aryl, orheterocyclyl; R¹⁰ is hydrogen or a group selected from alkyl and formylsubstituted with one or more, the same or different, alkyl, amino,hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, whereinR¹⁰ is optionally substituted with one or more, the same or different,R²⁰; R²⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R²⁰ is optionally substituted with one ormore, the same or different, R³⁰; R³⁰ is alkyl, halogen, nitro, cyano,hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy,alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl,arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R³⁰ isoptionally substituted with one or more, the same or different, R⁴⁰; andR⁴⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-di ethylcarbamoyl, N-methyl-N-ethylcarbamoyl,methylthio, ethylthio, methyl sulfinyl, ethyl sulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
 17. Thecompound of claim 16, wherein the compound is a compound of Formula IC,and wherein R²⁰ is heterocyclyl or alkyl substituted with a groupselected from amino and heterocyclyl.
 18. The compound of claim 17,wherein R²⁰ is substituted with one or more, the same or different, R³⁰.19. A method of reducing the symptoms of or delaying the progression ofstroke or traumatic brain injury, comprising administering an effectiveamount of a pharmaceutical composition comprising a compound of claim16.
 20. A compound selected from the group consisting of Formula 1D,Formula 1E, and Formula 1F:

or esters, prodrugs, or salts thereof wherein Z is O or S; m is 1, 2, 3,or 4; n is 1, 2, 3, or 4; R¹ is hydrogen, alkyl, halogen, nitro, cyano,hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy,alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl,arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R¹ isoptionally substituted with one or more, the same or different, R⁴; R²is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or R¹ and R² form a carbocyclic ring;R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴; R^(3′) is phosphate ion,hydrogen, —CH₂O(C═O)alkyl, or a group selected from alkyl, alkanoyl, andformyl further substituted with one or more, the same or different,alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, orheterocyclyl, wherein R^(3′) is optionally substituted with one or more,the same or different, R⁴; R⁴ is alkyl, halogen, nitro, cyano, hydroxy,amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy,alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl,arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R⁴ isoptionally substituted with one or more, the same or different, R⁵; andR⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dim ethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl; R⁹ and R¹⁰ and the attached nitrogenform a 5 or 6 membered heterocyclyl optionally substituted with one ormore, the same or different, R¹¹; or R⁹ is alkyl, alkoxy, alkylthio,alkylamino, (alkyl)₂amino, carbocyclyl, aryl, or heterocyclyl, whereinR⁹ is optionally substituted with one or more, the same or different,R¹¹; R¹⁰ is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,carbocyclyl, aryl, or heterocyclyl, wherein R¹⁰ is optionallysubstituted with one or more, the same or different, R¹¹; R¹¹ is alkyl,halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy,alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, orheterocyclyl, wherein R¹¹ is optionally substituted with one or more,the same or different, R¹²; R¹² is halogen, nitro, cyano, hydroxy,trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl,mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dim ethylcarbamoyl, N,N-di ethylcarbamoyl, N-methyl—N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl,N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, orheterocyclyl; R¹³ and R¹⁴ are the same or different alkyl optionallysubstituted with one or more, the same or different, R¹⁵; or R¹³ and R¹⁴and the attached carbon form a 5 or 6 membered aryl or heterocyclyloptionally substituted with one or more, the same or different, R¹⁵; R¹⁵is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹⁵ is optionally substituted with one ormore, the same or different, R¹⁶; and R¹⁶ is halogen, nitro, cyano,hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dim ethylcarbamoyl, N,N-di ethylcarbamoyl, N-methyl—N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl,N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, orheterocyclyl; R⁵⁰ and R⁶⁰ and the attached nitrogen form a 5 or 6membered heterocyclyl optionally substituted with one or more, the sameor different, R⁷⁰ or R⁵⁰ is alkyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, carbocyclyl, aryl, or heterocyclyl, wherein R⁵ isoptionally substituted with one or more, the same or different, R⁷⁰; R⁶⁰is alkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl,aryl, or heterocyclyl, wherein R⁶⁰ is optionally substituted with one ormore, the same or different, R⁷⁰; R⁷⁰ is alkyl, halogen, nitro, cyano,hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy,alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl,arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R⁷⁰ isoptionally substituted with one or more, the same or different, R⁸⁰; andR⁸⁰ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-di ethylcarbamoyl, N-methyl —N-ethylcarbamoyl,methylthio, ethylthio, methyl sulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-di methyl sulfamoyl, N,N-di ethyl sulfamoyl,N-methyl-N-ethyl sulfamoyl, carbocyclyl, aryl, or heterocyclyl.
 21. Thecompound of claim 20, wherein the compound is a compound of Formula IE,and wherein m is 0 or
 1. 22. The compound of claim 20, wherein thecompound is a compound of Formula IE, and wherein m is 2 or
 3. 23. Thecompound of claim 20, wherein the compound is a compound of Formula IE,and wherein R⁹ and R¹⁰ is morpholinyl, pyrrolidinyl, piperidinyl, orpiperazinyl ring.
 24. The compound of claim 23, wherein the morpholinyl,pyrrolidinyl, piperidinyl, or piperazinyl ring is further substitutedwith one or more, the same or different, R¹¹.
 25. A method of reducingthe symptoms of or delaying the progression of stroke or traumatic braininjury, comprising administering an effective amount of a pharmaceuticalcomposition comprising a compound of claim
 20. 26. A compound selectedfrom the group consisting of Formula 1H, Formula 11, Formula 1J, Formula1K, and Formula 1L:

or esters, prodrugs, or salts thereof wherein Z is O or S; m is 1, 2, 3,or 4; n is 1, 2, 3, or 4; R¹ is hydrogen, alkyl, halogen, nitro, cyano,hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy,alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl,arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R¹ isoptionally substituted with one or more, the same or different, R⁴; R²is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁴; or R¹ and R² form a carbocyclic ring;R³ is phosphate ion, hydrogen, —CH₂O(C═O)alkyl, or a group selected fromalkyl, alkanoyl, and formyl further substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R³ is optionally substituted withone or more, the same or different, R⁴; R^(3′) is phosphate ion,hydrogen, —CH₂O(C═O)alkyl, or a group selected from alkyl, alkanoyl, andformyl further substituted with one or more, the same or different,alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, orheterocyclyl, wherein R^(3′) is optionally substituted with one or more,the same or different, R⁴; R⁴ is alkyl, halogen, nitro, cyano, hydroxy,amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy,alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl,arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R⁴ isoptionally substituted with one or more, the same or different, R⁵; R⁵is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,tertbutyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetyl amino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dim ethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dim ethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethyl sulfamoyl,carbocyclyl, aryl, or heterocyclyl; wherein when the compound is acompound of Formula IH, Formula IJ, or Formula IJ, R¹⁰ is hydrogen or agroup selected from alkyl and formyl substituted with one or more, thesame or different, alkyl, amino, hydroxyl, thiol, halogen, aryl,carbocyclyl, or heterocyclyl, wherein R¹⁰ is optionally substituted withone or more, the same or different, R²⁰; R²⁰ is alkyl, halogen, nitro,cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl,alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R²⁰is optionally substituted with one or more, the same or different, R³⁰;wherein when the compound is a compound of Formula IK, R⁹ and R¹⁰ andthe attached nitrogen form a 5 or 6 membered heterocyclyl optionallysubstituted with one or more, the same or different, R¹¹; or R⁹ isalkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, carbocyclyl, aryl,or heterocyclyl, wherein R⁹ is optionally substituted with one or more,the same or different, R¹¹; R¹⁰ is alkyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, carbocyclyl, aryl, or heterocyclyl, wherein R¹⁰ isoptionally substituted with one or more, the same or different, R¹¹; R¹¹is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹¹ is optionally substituted with one ormore, the same or different, R¹²; R¹² is halogen, nitro, cyano, hydroxy,trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl,mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dim ethylcarbamoyl, N,N-di ethylcarbamoyl, N-methyl—N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl,N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, orheterocyclyl; R¹³ and R¹⁴ are the same or different alkyl optionallysubstituted with one or more, the same or different, R¹⁵; or R¹³ and R¹⁴and the attached carbon form a 5 or 6 membered aryl or heterocyclyloptionally substituted with one or more, the same or different, R¹⁵; R¹⁵is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹⁵ is optionally substituted with one ormore, the same or different, R¹⁶; R¹⁶ is halogen, nitro, cyano, hydroxy,trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl,mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-di methylcarbamoyl, N,N-di ethylcarbamoyl, N-methyl—N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl,N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, orheterocyclyl; R³⁰ is alkyl, halogen, nitro, cyano, hydroxy, amino,mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,alkylamino, (alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R³⁰ is optionallysubstituted with one or more, the same or different, R⁴⁰; and R⁴⁰ ishalogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl —N-ethylcarbamoyl, methylthio, ethylthio,methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl,carbocyclyl, aryl, or heterocyclyl.
 27. The compound of claim 26,wherein the compound is a compound of Formula IK, and wherein m is 0or
 1. 28. The compound of claim 26, wherein the compound is a compoundof Formula IK, and wherein m is 2 or
 3. 29. A method of reducing thesymptoms of or delaying the progression of stroke or traumatic braininjury, comprising administering an effective amount of a pharmaceuticalcomposition comprising a compound of claim
 26. 30. The method of claim29, wherein the pharmaceutical composition is administered to a subjectthat incurred trauma to the head or other organ or tissue.
 31. Themethod of claim 29, wherein the pharmaceutical composition isadministered after a medical procedure.
 32. The method of claim 29,wherein the pharmaceutical composition is administered in combinationwith a second anti-inflammatory agent.